PSYC 413 LECTURE NOTES
CH.18
III-17
a. The classic antipsychotics are the phenothiazines (such as chlorpromazine, or
Thorazine) and the butyropherones (such as haloperidol, or Haldol). The secondgeneration antipsychotics include clozapine (Clozaril) and risperidone (Risperdal).
b. Antipsychotics are only slowly and incompletely absorbed from the gastrointestinal
tract. Still, they tend to be administered orally because they are used over extended
periods of time. The drugs are administered via intramuscular injection, they are
released into the system so slowly that administration is needed only every 4-6 weeks.
Metabolism is slow and the half-life of these drugs ranges from 11 to 58 hours.
c. Classic antipsychotics (or neuroleptics) tend to antagonize dopamine transmission by
competitively blocking DA receptors or by inhibiting DA release. They show a high
affinity for D2 receptors, which serve as both normal postsynaptic receptors and
autoreceptors in the basal ganglia, nucleus accumbens, amygdala, hippocampus, and
cerebral cortex. Some of the second-generation antipsychotics can also act as
serotonin antagonists.
d. Homovanillic acid (HVA) is a principal DA metabolite. Clinical response to
antipsychotic treatment produces an increase in HVA, indicating an initial increase in
dopamine metabolism. This is followed by a gradual decrease in HVA with chronic
treatment.
e.
1. The mesolimbic pathway projects from the ventral tegmental area to the nucleus
accumbens and other limbic areas.
2. The mesocortical pathway also projects from the VTA but sends axons to the limbic
cortex.
3. The nigrostriatal pathway begins in the substantia nigra and projects to the striatum.
4. The tuberohypophyseal pathway begins in the hypothalamus and projects to he
pituitary gland, where it regulates pituitary hormone secretion.
f. The most serious side effect of the classic antipsychotics are the movement disorders
that resemble the symptoms of Parkinson’s disease. These include tremors, akinesia (a
slowing or loss of voluntary movements), muscle rigidity, akathesia (a strong feeling of
discomfort in the legs and an inability to sit still), and a loss of facial expression. A
second type of motor side effect is tardive dyskinesia, which is characterized by
stereotyped, involuntary movements, particularly of the face and jaw but also of the
arms, legs, trunk, and neck. There can be neuroendocrine effects such as breast
enlargement and tenderness, decreased sex drive, lack of menstruation, increased
release of prolactin, and inhibition of growth hormone release, which can be a serious
issue when medicating children and adolescents. A relatively lethal condition called
neuroleptic malignant syndrome may also occur, characterized by rigidity, altered
consciousness, and autonomic nervous system instability (including rapid heart rate and
fluctuations in blood pressure). Antipsychotic drugs can also have anti-cholinergic (dry
mouth, blurred vision, constipation, difficulty in urination, and decreased gastric
secretion and motility) and anti-adrenergic (sedation and low blood pressure that can
lead to dizziness, faintness, and blackouts) effects.
g. Unlike classical antipsychotic, second-generation antipsychotics:
1. can reduce symptoms of schizophrenia without causing significant extrapyramidal
side effects
2. do not produce the predicted results in behavioral screening tests
3. can reduce negative as well as positive symptoms and are effective in treatmentresistant patients
h.
1. Selective D2 receptor antagonists: Their selectivity for DA receptors minimizes their
effects on the autonomic nervous system and cardiovascular system. However,
hormonal side effects tend to be common, and the risk of fatal blood disorders reduces
the utility of the drugs.
2. Broad-spectrum antipsychotics: This class of drugs blocks other types of receptors in
addition to D2 receptors. Clozapine and risperidone act as serotonin antagonists.
Although clozapine is no more effective than classic antipsychotics in treating the
positive symptoms of schizophrenia, it is often effective in patients who do not respond
to classic antipsychotic treatment. It can also reduce negative symptoms as well as
anxiety and tension. Unfortunately, it has a wide variety of side effects, increasing the
risk of seizures and producing hypersalivation, weight gain, cardiovascular problems,
and a blood abnormality called agranulocytosis. Risperidone has many of the benefits
of clozapine without the risk of blood disorders. The most common side effects with
risperidone are insomnia, anxiety, agitation, sedation, dizziness, hypotension, weight
gain, and menstrual disturbances. It also increase the risk of diabetes.
3. Dopamine system stabilizers: Some of these drugs are dopamine agonistsantagonists, which means that they bind readily to DA receptors but produce less of an
effect than DA itself. They reduce both the positive and negative symptoms of
schizophrenia with minimal side effects.
III-18
a.
1. Dopamine hypothesis: Amphetamines can produce a psychotic reaction in healthy
individuals that can be reversed by DA antagonists. Also, schizophrenics report that
cocaine and amphetamine make their symptoms worse. There is a correlation between
D2 receptor blockade and reduction of symptoms, and antipsychotic treatment induces
changes in DA turnover.
2. Neurodevelopmental model: The negative symptoms of schizophrenia resemble the
characteristics of patients with lesions of the frontal lobe. Also, the severity of these
symptoms is correlated with reduced prefrontal cell metabolism. There is a correlation
between poor neuropsychological test performance on tasks requiring frontal lobe
function, reduced cerebral blood flow in the prefrontal cortex, and decreased DA
function. When the inhibitory cortical feedback is lost, mesolimbic cells increase their
activity. Psychotic experiences, hallucinations, perceptual distortions, and irrational
fears are associated with electrical discharge in the limbic regions of epileptic patients.
3. Glutamate-dopamine hypothesis: Loss of glutamate input to sub-cortical DA centers
leads to excess DA activity and the positive symptoms of schizophrenia. There is
evidence of low glutamate levels and reduced glutamate release in schizophrenics, as
well as changes in glutamate receptors in several brain areas. Some antipsychotics
such as clozapine and haloperidol modify glutamate function.
CH.17
III-15
a. All of these drugs reduce neuron excitability by enhancing the inhibitory effects of
GABA. On a subjective level, they relieve the feelings of tension, worry, and stress that
are typical of anxious individuals, producing a calm and relaxed state, with side effects
that include drowsiness and mental clouding, incoordination, and prolonged reaction
time. At higher doses, these drugs can also induce sleep, coma, or death.
b.
1. ultrashort-acting: highly lipid soluble, can penetrate brain to put an individual to sleep
within 10-20 seconds when administered intravenously, with consciousness returning in
20-30 minutes; includes thiopental (Pentothal) and hexobarbital (Evipal)
2. short/intermediate-acting: moderately lipid soluble, producing relaxation and sleep in
about 20-40 minutes and lasting 5-8 hours; includes amobarbital (Amytal) and
secobarbital (Seconal)
3. long-lasting: have poor lipid solubility so that their onset takes an hour or more and
their action lasts 10-12 hours; used to treat seizure disorders; includes Phenobarbital
(Luminal)
c. The side effects of barbiturates include:
1. a reduction in REM sleep
2. cognitive side effects that include mental clouding, loss of judgment, and slowed
reflexes
3. an increase in the number of liver microsomal enzymes, resulting in metabolic
tolerance and reduced effectiveness
4. physical dependence and potential for abuse
d. Oral ingestion of high doses in a binge fashion may be a substitute for alcohol or may
occur in combination with alcohol to enhance the effect. Other users inject the
barbiturate intravenously to produce a “high” similar to that achieved with heroin.
Injected barbiturates may then replace heroin if the preferred drug is not available, or
the two may be used in combination. Simultaneous use of a CNS stimulant like
amphetamine and a barbiturate may produce an unusual mood elevation that is
considered “smoother” than with the stimulant alone.
e. BDZs are useful for presurgical anesthesia during which the patient is conscious but
less aware of his/her surroundings and quite relaxed. They are also commonly used
before major dental work as well as for a wide range of stressful diagnostic procedures.
But the most common use is for anxiety relief. Several of the longer-acting BDZ are
also used as hypnotics, shortening the time needed to fall asleep and increasing the
duration of sleep time. Some BDZs are useful muscle relaxants and other are anticonvulsants. They can also be used to prevent acute alcohol or barbiturate withdrawal
symtoms.
f. BDZs relieve the sense of worry and fearfulness as well as the physical symptoms
associated with anxiety with less mental clouding, loss of judgment, and motor
incoordination than barbiturates. Their anti-anxiety effects show little or no tolerance.
BDZs have a higher therapeutic index than other sedative-hypnotics, they rarely
produce lethal overdose because they have almost no effect on the respiratory center in
the medulla, and they do not increase the number of liver microsomal enzymes that
normally lead to metabolic tolerance.
g. The abstinence syndrome is relatively mild and develops gradually over several
weeks. Symptoms include insomnia, restlessness, headache, anxiety, mild depression,
subtle perceptual distortions, muscle pain, and muscle twitches. The most severe
symptoms, which resemble those of other CNS depressants, include panic, delirium,
and seizures. Those occur in individuals who are abusing the drugs at high doses for
prolonged periods, often in combination with other drugs.
h. Buspirone is much less effective in reducing the physical symptoms of anxiety than
the cognitive aspects of worry and poor concentration. It has several advantages over
BDZs, including its usefulness in treating depression that often accompanies anxiety. In
addition, its anxiety reduction is not accompanied by sedation, confusion, or mental
clouding. Buspirone does not enhance the CNS-depressant effects of alcohol or other
depressants. It also has a minimum of severe side effects, and fatalities have not been
reported. It has little potential for recreational use or dependence and no rebound
withdrawal syndrome.
One downside of buspirone is that its onset is quite long, requiring several weeks of
daily use. Because it has no cross-tolerance with other sedative-hypnotics, it cannot be
used as a replacement drug for those experiencing alcohol or barbiturate withdrawal. It
lacks the hypnotic effects needed to treat insomnia, does not control seizures, and has
no muscle-relaxant effect.
i. The effectiveness of the SSRIs in treating OCD is believed to be related to their ability
to enhance serotonin function.
III-16
a. GABA is the major inhibitory neurotransmitter in the nervous system. It has receptors
on most cells in the CNS. The GABAA receptor complex opens chloride channels and
thus causes hyperpolarization of the cell.
b. When BDZs bind to their receptor on the GABAA complex, they enhance the effect of
GABA by increasing the number of times the chloride channel opens. However, in the
absence of GABA, BDZs have no effect. Barbiturates also increase the affinity of the
GABAA receptor complex for GABA, but they increase the duration of the opening of
GABA-activated chloride channels rather than the number of openings. In addition, they
also directly open the chloride channels without GABA.
c. The central nucleus of the amygdala orchestrates the components of anxiety,
including: autonomic activation, defensive behavior, enhanced reflexes, and activation
of the HPA axis. It is associated with the identification of the emotional significance of
events and aids in the formation of emotional memories.
The prefrontal cortex exerts inhibitory control over the more primitive responses of the
limbic system. Without this “cognitive” control, the anxiety response produces more
limited patterns of behavior that may not be suitable for coping with modern stressors
that are not resolved by a fight-or-flight response.
d. Local administration of GABA or a GABA agonist into the amygdala reduces anxiety.
e. BDZs can still have anxiety-reducing effects following destruction of the amygdala,
suggesting that other brain areas are also involved.
f. Inverse agonists can bind to the BDZ site and produce the opposite actions of the
drugs, namely increased anxiety, arousal, and seizures. These inverse agonists are
presumed to uncouple the GABA receptors from the chloride channels so that GABA is
less effective in causing entry of chloride into the cell.
Other ligands called endozepines may represent natural anxiety-reducing agents that
act at the BDZ site. When individuals lean to cope with stress, anxiety may be reduced
by the action of these ligands.
g. In patients with panic disorder, PET scans show less BDZ binding in the CNS,
particularly in portions of the frontal lobes. These patients are also less sensitive to
BDZs on several psychophysiological measures.
h. Norepinephrine—The locus coeruleus, where noradrenergic neurons are located,
forms reciprocal connections with the amygdala. The LC shows increased firing rates
when animals are presented with novel stimuli that signal either threat or reward.
Anxiety disorders have been linked to abnormal autonomic response, including higherthan-normal circulating NE. NE has a significant role in the formation of emotional
memories, and some anxieolytic drugs work by modulating the firing of cells in the LC.
Corticotrophin-releasing factor (CRF)—This hormone controls the HPA axis and
behavioral responses to stress and anxiety. Injecting CRF into the ventricles stimulates
sympathetic nervous system activity. There are large numbers of CRF receptors in the
amygdala, and stressful stimuli produce a release of CRF in the amygdala. Veterans
with PTSD have higher-than-normal CRF levels in their cerebrospinal fluid. Injection of
CRF into the cranium increases the firing rate of cells in the LC and increased NE
turnover.
Dopamine—Stress can increase the firing rate of mesocortical dopaminergic cells and
increases DA turnover in the prefrontal cortex. Anxiety-producing drugs can increase
DA metabolism in the prefrontal cortex without causing changes in DA terminals within
the mesolimbic or nigrostriatal tracts.
Serotonin—SSRIs desensitize terminal 5-HT autoreceptors in the orbitofrontal cortex,
causing an increased release of 5-HT into synapses.
CH.16
III-14
a.
1. monoamine oxidase inhibitors
2. tricyclic antidepressants
3. second-generation antidepressants (selective serotonin reuptake inhibitors and
atypical antidepressants)
b. With appropriate dietary restrictions, MAO-Is can be used safely and often work well
for patients who are treatment resistant and who reject the idea of electroconvulsive
therapy. In addition, they are also used in the treatment of anxiety and have positive
effects in the treatment of bulimia and anorexia nervosa.
c. By inhibiting MAO, these drugs increase the amount of monoamine neurotransmitters
(NE, DA, and 5-HT) available for release into the synapse.
The more common side effects include changes in blood pressure, sleep disturbances
(including insomnia), and overeating—especially of carbohydrates—which may lead to
excessive weight gain). MAO-Is also enhance the effect of any drug that enhances NE
function, which can produce symptoms such as sweating, elevated blood pressure, and
increased body temperature. Some serious side effects are due to the inhibition of
MAO in the liver, which is responsible for deaminating tyramine—a naturally occurring
amine formed as a by-product of fermentation in many foods, including cheeses, certain
meats, and pickled foods. These foods must be avoided by individuals taking MAO-Is.
Elevated tyramine levels release the higher-than-normal stores of NE at nerve endings,
causing a dramatic increase in blood pressure. MAO-Is also inhibit other liver enzymes
such as cytochrome P450, which normally degrade such drugs as barbiturates, alcohol,
opiates, and aspirin. The effects of these drugs can be prolonged and intensified in the
presence of MAO-Is.
d. Tricyclic antidepressants inhibit the reuptake of NE and/or 5-HT. These drugs can
also block histamine, acetylcholine and alpha-adrenergic receptors. The blockade of
histamine receptors produces the sedation and fatigue that are frequent side effects.
Anticholinergic side effects can include dry mouth, constipation, urinary retention,
dizziness, confusion, impaired memory, and blurred vision. And alpha-adrenergic
blockade in combination with the NE reuptake-blocking effects lead to several
potentially dangerous cardiovascular side effects, including orthostatic hypotension,
tachycardia, and arrhythmias. Toxicity following overdose causes cardiovascular
depression, delirium, convulsions, respiratory depression and coma. Heart arrhythmias
may produce cardiac arrest and fatalities.
e. SSRIs block the reuptake of 5-HT almost exclusively, with very little effect on NE
reuptake. The side effects of SSRIs are different than those of the TCAs because they
have no effect on NE, histamine, or acetylcholine receptors. Side effects include:
anxiety, restlessness, movement disorders, muscle rigidity, nausea, headache,
insomnia, and sexual dysfunction, which occurs in 40-70% of patients. They can have
life-threatening effects when combined with other serotonergic agonists or drugs that
interfere with normal metabolism of the SSRIs. These symptoms, referred to as the
serotonin syndrome, are characterized by severe agitation, disorientation and
confusion, ataxia, muscle spasms and exaggerated autonomic nervous system
functions including fever, shivering, chills, diarrhea, elevated blood pressure, and
increased heart rate.
f. ECT enhances the function of several neurotransmitter systems, including NE, 5-HT,
DA, and GABA, and these changes are probably responsible for its antidepressant
effects. The most significant side effect is cognitive impairment, taking the form of
confusion and memory loss. ECT may disrupt the ability to retain new information
(anterograde amnesia) for several days or weeks after treatment. In addition, significant
retrograde amnesia for events preceding the treatment may also occur.
g. Lithium enhances 5-HT activity, elevating brain tryptophan, 5-HT, and 5-HIAA levels,
as well as increasing 5-HT release, which ultimately alters receptor response in several
brain areas. Lithium reduces catecholamine activity by enhancing reuptake and
reducing release. Because it is not metabolized but is excreted by the kidneys in its
intact form at a rate inversely related to sodium levels, sodium depletion (due to
extreme sweating, diarrhea, vomiting, dehydration, etc) may lead to potentially toxic
levels of lithium. Side effects are generally mild but may include increased thirst and
urination, impaired concentration and memory, fatigue, tremor, and weight gain. Toxic
effects are more severe and include camps, vomiting, diarrhea, kidney dysfunction,
coarse tremor, confusion, and irritability.
CH.14
III-12
a. Mescaline—The peyote cactus, which is found in the Southwestern United States
and Mexico, is the source of mescaline. The crown of the peyote cactus, known as a
peyote button, is cut off and dried. It is then chewed raw or cooked and then eaten. Or
mescaline can be extracted from the catctus and consumed as a relatively pure powder.
Psilocybin—Certain types of mushrooms, such as the genus Psilocybe, are either eaten
raw, boiled in water to make tea, or cooked with other foods to cover the bitter flavor.
Dimethyltryptamine (DMT)—This substance and its analog 5-MeO-DMT, are found in a
number of plants that are indigenous to South America. Indigenous tribes there make
hallucinogenic snuffs or drinks such as ayahuasca. In the U.S., DMT is sold in
powdered form and taken by smoking.
b. Albert Hofmann first synthesized LSD (d-lysergic acid diethylamide) from ergot, a
substance produced by a parasitic fungus, believing it would be useful as a respiratory
stimulant. Instead, he accidentally discovered its hallucinogenic properties. At first, LSD
was used as a psychotherapeutic tool to uncover repressed thoughts and feelings. It
was also used in the U.S. and Canada as a form of “psychedelic therapy,” intended to
help patients gain insights into their problems. The US government considered using it
as a mind control agent. LSD’s popularity exploded because of the experimentation of
Harvard University psychologist Timothy Leary and the “acid tests” conducted by author
Ken Kesey and his band of “merry pranksters.” Recreational use of LSD was banned in
1967.
III-13
a. The psychedelic effects of most hallucinogens generally begin within 30 to 90
minutes of ingestion. An LSD or mescaline “trip” typically lasts 6-12 hours or even
longer, whereas psilocybin’s effects may dissipate a bit sooner. The effects of smoked
DMT are felt within seconds, reach a peak by 5-20 minutes, and are over within an hour
or less.
b. 1. Onset—occurs about 30-60 minutes after ingestion; visual effects include
intensification of colors and appearance of geometric patterns that can be seen with
one’s eyes closed. 2. Plateau—the next two hours; subjective sense of time slows
down, visual effects become more intense. 3. Peak—generally occurs after three hours
and lasts 2-3 hours; characterized by feelings of being in another world, time standing
still, bizarre images, possibly synesthesia. 4. Come-down—a phase lasting for two or
more hours, in which most of the effects dissipate.
c. Most hallucinogenic drugs have either a serotonin-like or catecholamine-like
structure. The serotonin-like (or indoleamine) hallucinogens include LSD, psilocybin,
psilocin, DMT, 5-MeO-DMT. Mescaline is a catecholamine-like (phenethylamine)
hallucinogen.
d. LSD is a serotonin agonist that binds to at least eight different serotonergic receptor
subtypes.
e. Volenweider et al (1998) showed that the visual illusions and hallucinations produced
by psilocybin can be blocked by 5-HT2A antagonists (such as risperidone).
f. Most hallucinogens, with the exception of DMT, produce rapid tolerance, probably due
to down-regulation of 5-HT2A receptors.
g. One hypothesis is that hallucinogens decrease the spontaneous firing of cells in the
locus coeruleus (which receives and integrates input from all of the major sensory
systems and sends information to all areas of the cortex) and at the same time
enhances the excitability of these cells by sensory stimulation. An alternative
hypothesis is that hallucinogens disrupt normal information processing in a circuit that
includes the frontal cortex, striatum, and thalamus. This hypothesis argues that
hallucinogens interfere with the normal screening or “gating” of sensory information
passing through this circuit, resulting in information overload at the cortical level.
h. Hallucinogens are not considered addictive in the standard sense. Users do not
binge on them, and it is rare for people to experience the kind of cravings seen with
addictive drugs such as cocaine and opiates. They also do not produce physical
dependence or withdrawal and are not effective reinforcers in animal tests.
i. The most common problem associated with hallucinogens is the occurrence of “bad
trips,” which are probably an interaction between the drug, the individual’s emotional
state at the start of the drug experience, and the external environment. Another
problem is flashbacks, which is defined in the DSM-IV as “the re-experiencing, following
cessation of use of a hallucinogen, of one or more of the perceptual symptoms that
were experienced while intoxicated.” With LSD there is also the potential for a
psychotic breakdown, which generally occurs in individuals who had already been
diagnosed with a psychotic disorder or who had experienced pre-psychotic symptoms
before taking the drug.
CH.13III-9
a. Marijuana—the crude mixture of dried and crumbled leaves, small stems, and
flowering tops from the Cannabis sativa plant. Hashish—a relatively pure resin
preparation with a very high cannabinoid content, or solvent extracts of leaves or resin
that are more variable in their potency.
b. Most studies have not found a correlation between breath-hold duration and
subjective “high,” although Block et al found a small yet significant difference between
durations of seven and 15 seconds.
c. Smoking THC produces rapidly rising levels in the blood plasma of the smoker once
the THC is absorbed through the lungs. After reaching a relatively fast peak, THC
levels decline due to a combination of metabolism in the liver and accumulation of the
drug in the body’s fat stores. In contrast, oral consumption leads to prolonged but poor
absorption of THC from the gastrointestinal tract, thus resulting in low and variable
plasma concentrations that increase much more slowly.
d. Cannabinoid receptors are found in the basal ganglia (including the striatum, globus
pallidus, and substantia nigra), cerebellum, hippocampus and cerebral cortex.
e. CB1 receptors, which are found in the CNS, are metabotropic and tend to result in an
inhibition of cyclic AMP formation, inhibition of calcium channels, and activation of
potassium channels. They tend to be found on axon terminals instead of postsynaptic
receptors, and thus inhibit the release of many different neurotransmitters, including
acetylcholine, dopamine, norepinephrine, serotonin, glutamate, and GABA.
f. The endocannabinoids are too lipid soluble to be stored in vesicles since they would
just pass right through the vesicle membrane. And so they are probably just made and
released when needed.
g. Endocannabinoid release is triggered by an increase in intracellular calcium levels.
After their release, they are taken up by a specific transport protein and then
metabolized by several enzymes, such as fatty acid amide hydrolase (FAAH).
h. Endocannabinoids may act as retrograde messengers at specific synapses in the
hippocampus and cerebellum, carrying information from the postsynaptic to the
presynaptic cell. In response to depolarization of the postsynaptic cell, they get
released and cross the synaptic cleft, where they inhibit neurotransmitter release from
the presynaptic neuron. For instance, in the hippocampus, endocannabinoids are
released by pyramidal cells and inhibit release of GABA from interneurons that would
normally suppress the firing of these pyramidal cells. The inhibition of GABA permits
the pyramidal cell to temporarily fire at a faster-than-normal rate.
III-10
a. 1. The “buzz”—a brief period during which the user may feel lightheaded or even
dizzy, and may experience tingling in different parts of the body. 2. The “high”—
characterized by feelings of euphoria and exhileration, as well as a sense of
disinhibition that is often manifested as increased laughter. 3. Being “stoned”—the
user feels calm, relaxed, perhaps even in a dreamlike state; sensory reactions
experienced in this stage include floating sensations, enhanced visual and auditory
perception, visual illusions, and a tremendous slowing of time. 4. The “come-down”—
the effects of the drug wear off.
b. There is increased blood flow to the skin, which leads to sensations of warmth or
flushing. Heart rate and appetite may be stimulated, as well.
c. Marijuana can evoke a psychopathological response in a small percentage of users,
including strong feelings of anxiety or panic, feelings of paranoia, and delirium (most
commonly be first-time users). Also, flashbacks have occasionally been reported.
d. In a study by Kirk et al, the expectation of consuming cannabinoids not only
enhanced the pleasurable effects of actual cannabinoid administration but it also elicited
a more positive response from subjects given a placebo. Also, there is evidence that
the maximum level of intoxication occurs when plasma THC levels are already
declining.
e. Either the brain has a delay reaction in processing information related to THC, or the
metabolites of THC contribute in some way to the psychoactive properties of the drug.
f. Cognitive—Marijuana intoxication produces illogical or disordered thinking,
fragmented speech, and difficulty in remaining focused on a given topic of conversation,
as well as deficits in a variety of verbal, spatial, time estimation, and reaction time tasks.
Psychomotor—Marijuana can impair tasks such as driving an automobile.
g. Regular marijuana users can discriminate cigarettes containing THC from ones
containing placebo. Subjects preferred THC cigarettes or capsules over their placebocontaining analogs.
h. Cannabinoids stimulate firing of DA neurons in the VTA and the release of DA in the
nucleus accumbens. Mu-opioid receptors mediate the rewarding effects of
cannabinoids whereas kappa-opioid receptors mediate the aversive effects.
i. Endocannabinoid systems may play a role in the process of reinforcement,
dependence and relapse for a number of other drugs, including ethanol, opioids,
cocaine and nicotine.
III-11
a. Prior experience with alcohol and tobacco, emotional problems in the family, heavy
drug use in the household and/or by peers, dislike of school, poor school performance,
and an early age of first use of marijuana are all risk factors in the development of
heavy marijuana use by adolescents.
b. Some investigators have observed tolerance following repeated administration of
THC to subjects, whereas others have reported that the “high” produced by THC is
similar in heavy and light users.
c. Dependence—difficulty in stopping drug use, a craving for marijuana, and unpleasant
withdrawal symptoms. Withdrawal—irritability, increased anxiety, depressed mood,
sleep disturbances, heightened aggressiveness, and decreased appetite.
d. Decreased DA cell firing in the VTA and increased corticotrophin-releasing factor in
the amygdale by be linked to marijuana abstinence syndrome.
e. Dependent THC users typically enter outpatient programs that involve cognitivebehavioral therapy, relapse prevention training, and motivational enhancement therapy.
These approaches can be combined with an incentive program in which participants
earn vouchers for THC-free urine samples.
f. In younger users, greater THC use is associated with poorer grades, more negative
attitudes about school and increased absenteeism. It can produce amotivational
syndrome. When consumed by smoking, it can produce lung damage. Tar from
cannabis smoke actually contains higher concentrations of certain carcinogens than
tobacco. Cannabinoid use can suppress immune function and can possibly have
reproductive effects (reduced sperm count in men; suppressed release of luteinizing
hormone in women).
CH.12III-6
a. Smoking has such a powerful reinforcing effect because it can deliver nicotine to the
brain in about seven seconds, which is about twice as fast as an intravenous injection.
b. Most nicotine is broken down into cotinine by the liver enzyme, cytochrome P450
2A6. Cotinine and other nicotine metabolites are excreted mainly in the urine.
c. Nicotine works mainly by activating nicotinic cholinergic receptors, which are
ionotropic receptors found in many parts of the brain, including the cerebral cortex,
thalamus, striatum, hippocampus, substantia nigra, ventral tegmental area, locus
coeruleus, and raphe nuclei. When nicotine binds to nicotinic receptors, it opens sodium
and calcium channels.
d. Mood: Nicotine is usually found to increase calmness and relaxation in abstinent
smokers, probably due to relief from nicotine withdrawal symptoms. In non-smokers,
nicotine elicits feelings of heightened tension or arousal along with light-headedness,
dizziness, and nausea.
Cognition: Abstinent smokers given nicotine show enhanced performance on many
kinds of cognitive tasks, especially those involving attention. Much of this enhancement
may be due to the alleviation of withdrawal-related deficits. Yet there is some indication
that nicotine has positive effects on cognitive performance even in non-smokers,
reducing reaction times on visual attention tasks.
e. Nicotine receptors located in the VTA stimulate the firing of dopaminergic neurons,
which causes increased DA release in the nucleus accumbens.
f. Nicotine activates elements of both the sympathetic and parasympathetic nervous
system, causing the adrenals to release epinephrine and norepinephrine and activating
sympathetic ganglia. This activation elevates blood pressure and can increase a
smoker’s risk for cardiovascular disease and strokes. The action of nicotine on
parasympathetic ganglia increases hydrochloric acid secretion in the stomach and
muscle contractions in the bowel.
g. The symptoms of nicotine poisoning include nausea, excessive salivation, abdominal
pain, vomiting, diarrhea, cold sweat, headaches, dizziness, disturbed hearing and
vision, mental confusion, weakness, fainting, a drop in blood pressure, difficulty
breathing, irregular heart rate, and even respiratory failure.
h. Nicotine produces acute tolerance that wears off during the night, which is why
smokers often report that their first cigarette of the day tends to be the most
pleasurable.
i. Foulds et al (1997) showed that a subcutaneous injection of nicotine produced
symptoms of mild nicotine toxicity in non-smokers but not in smokers. This suggests
that smokers have developed a tolerance to the toxic effects of nicotine, and also that
this tolerance must occur before an individual can fully experience nicotine’s reinforcing
effects.
j. The nicotine abstinence syndrome is mediated by nicotinic receptors in both the
central nervous system (VTA) and peripheral nervous system (autonomic ganglia).
III-7
a. More than 70 million Americans were using tobacco as of 2002, which is
approximately 30% of the population age 12 and older. The highest incidence of
tobacco use is in the 18-25-year age range. Males are more likely to smoke than
females, and the highest rate of smoking is among Native Americans, followed by
whites, Hispanics, African Americans and then Asians. There is an inverse correlation
between smoking and education.
b. Teenagers may take up smoking for any of the following reasons: establishing
feelings of independence and maturity; improving self-image and enhancing social
acceptance; counteracting stress and boredom; curiosity.
c. The fact that cigarettes devoid of nicotine have never been popular is evidence that
nicotine is a big part of the reason why people smoke. Also, people smoke more when
they switch from regular cigarettes to ones low in tar and nicotine.
d. Nicotine abstinence syndrome is characterized by tobacco craving, irritability,
impatience, restlessness, anxiety, insomnia, difficulty concentrating, hunger and weight
gain.
e. Sensory stimuli associated with smoking, such as the taste and smell of inhaling
cigarette smoke, can become conditioned to the reinforcing effects of nicotine and are
thus able to function as secondary reinforcers themselves. Also, brain imaging studies
have shown that smokers have less MAO activity compared to non-smokers,
suggesting that some ingredient in cigarettes acts as an MAO inhibitor.
f. Cigarette smoking increases the risk of many life-threatening illnesses, including
cancer, cardiovascular disease, respiratory diseases (e.g., emphysema and chronic
bronchitis). Smokers are at an increased risk for heart attack, stroke, and
atherosclerosis. Smoking during pregnancy is the leading cause of low birth weight,
which can lead to other complications.
g. Behavioral interventions are often focused on smoking prevention, through media
campaigns, warnings on cigarette packages, and high taxes. There are various self-help
strategies that are limited in their effectiveness, although individual and group
counseling programs can be more successful—especially those that provide social
support and coping-skills training to their clients.
The most common pharmacological intervention for smoking cessation is nicotine
replacement, such as nicotine gum, transdermal patches, nicotine spray, and lozenges.
When combined with buproprion (Zyban), an antidepressant that inhibits DA and
norepinephrine reuptake, the effectiveness of nicotine replacement increases
considerably.
III-8
a. Caffeine is completely absorbed from the gastrointestinal tract within 30-60 minutes.
Caffeine absorption begins in the stomach but takes place mainly within the small
intestine. About 1-2% of an administered dose is excreted unchanged. In humans,
virtually all caffeine is broken down into its metabolites and then eliminated through the
urine (95%), feces, and bodily fluids such as saliva.
b. In animals, low doses have a stimulant effect, producing increased locomotor activity;
at high doses, this effect is reversed and animals actually show reduced activity. In
humans, low doses can have positive subjective effects (feelings of well-being,
enhanced energy, increased alertness and self-confidence, and enhanced sociability),
whereas high doses produce feelings of tension and anxiety.
c. Some of caffeine’s subjective effects may be related to its peripheral physiological
actions. These include increased blood pressure and respiration rate, enhanced
excretion, and stimulation of catecholamine release (especially epinephrine).
d. Two therapeutic uses of caffeine are: It is found in some over-the-counter analgesic
agents because it has been shown to be mildly effective in the treatment of nonmigraine headache. Caffeine is also used to regularize breathing in newborn infants
with breathing irregularities.
e. Heavy coffee drinkers can consume caffeine shortly before bedtime and still fall
asleep, whereas a late-night cup of coffee is likely to cause insomnia in someone who
does not normally consume much caffeine. Chronic caffeine use also produces
tolerance to the cardiovascular and respiratory effects of the drug.
f. Caffeine withdrawal symptoms include headache, drowsiness, fatigue, impaired
concentration and psychomotor performance, and in some cases, mild anxiety and
depression. Intense coffee cravings may also occur.
g. Heavy coffee drinking has been linked with increased blood pressure and a
heightened risk of coronary heart disease. Caffeine consumption by pregnant women
can also lead to low infant birth weight.
h. Caffeine has several mechanisms of action. It blocks the enzyme that breaks down
cAMP, as well as GABA and adenosine receptors. It can also stimulate calcium release
in cells. The blockade of adenosine receptors may be the most important in terms of
producing the subjective effects associated with caffeine consumption.
i. Adenosine is a neurotransmitter that is believed to be responsible for feelings of
drowsiness following periods of prolonged wakefulness.
CH.11III-1
a. Source of cocaine: the coca shrub, native to South America. Method of production:
After extraction, it is converted to a hydrochloride salt that can be crystallized. Cocaine
hydrochloride is water soluble and breaks down when exposed to heat. To avoid this
breakdown, the salt is transformed back into cocaine freebase by one of two different
methods. The first involves treating the hydrochloride salt with an alkaline solution and
then dissolving it in an organic base such as ether. Smoking cocaine obtained in this
manner is called freebasing. The second method involves mixing dissolved cocaine
HCl with baking soda, heating the mixture, and then drying it to form crack.
b. IV injection and smoking produce very rapid absorption of cocaine into the
bloodstream. Absorption is somewhat slower with oral administration or snorting.
c. Once cocaine is in the bloodstream, it gets broken down quickly by enzymes in the
bloodstream and liver. It is also eliminated rapidly, with a half life of 0.5-1.5 hours. That
is why the subjective high associated with cocaine tends to last only about 30 minutes.
d. When taken together, cocaine and alcohol produce a metabolite called cocaethylene,
which acts like cocaine but has a longer half-life. This can exacerbate the toxic effects
of cocaine on the heart and other organs.
e. Cocaine blocks the reuptake of three monoamine neurotransmitters: dopamine (DA),
norepinephrine (NE), and serotonin (5-HT). It binds to the transporters and thus inhibits
their function. The order of affinity of cocaine for transporters is: 5-HT > DA > NE. The
blockade of DA transporters seems to be the most important for predicting cocaine’s
stimulating, reinforcing, and addictive properties.
f. At higher concentrations, cocaine can act as a local anesthetic by blocking sodium
channels. Two synthetic local anesthetics used commonly in medical and dental
practice—procaine (Novocain) and lidocaine (Xylocaine)—were developed from the
structure of cocaine.
II-2
a. Typical aspects of the cocaine “high” are feelings of exhileration and euphoria, a
sense of well-being, enhanced alertness, heightened energy, diminished fatigue, and
increased self-confidence. Taken by IV injection or smoking, it also produces a brief
“rush” described by some as orgasm-like. At lower doses, it increases sociability and
sexual arousal, as well as aggressive behavior.
b. Cocaine is sympathomimetic, which means that it produces symptoms of sympathetic
nervous system arousal. The physiological consequences of acute administration of
cocaine include: increased heart rate, vasoconstriction, increased blood pressure, and
increased body temperature. High does can be toxic and even fatal. Some of the
potential conseuqnces of heavy cocaine use are seizures, heart falure, stroke, or
intracranial hemorrhaging.
c. Cocaine blocks DA uptake whereas amphetamine also stimulates DA release.
Cocaine produces local anesthetic effects whereas amphetamine does not.
d. The rewarding and reinforcing effects of cocaine depend not only on the blockade of
dopamine transporters (DAT) by cocaine but also on the interaction of the drug with
other molecular targets.
e. Volkow et al have used PET imaging to estimate DAT occupancy by cocaine or
methylphenidate (Ritalin). When DAT occupancy reaches a minimum level (40-60%),
the subject tends to experience a drug-induced “high.” However, the intensity and
likelihood of the “high” depend not just on DAT occupancy but also on the rate at which
the drug binds to the transporter and also the baseline level of DA activity in the
mesolimbic pathway. Higher baseline levels and faster occupancy rates tend to produce
a more intense “high.”
f. D1 receptors are linked to the locomotor-stimulating effects of cocaine, whereas D2
receptors are linked to the reinforcing effects.
III-3
a. The long-term abuse potential of the drug depends on early use of other substances,
the availability of the drug, cost, the social and legal consequences of drug use, and the
fear of losing control over one’s drug use.
b. Psychomotor stimulants can produce either tolerance or sensitization, depending on
the pattern of drug administration. Continuous administration of the drug produces
tolerance, whereas once-daily use produces sensitization.
c. There are two phases of sensitization: In the induction phase, sensitization is
established, and in the expression phase, the sensitized response is manifested.
Activation of glutamate NMDA receptors and D1 receptors is necessary for the induction
of sensitization, whereas expression is dependent at least partly on enhanced reactivity
of dopaminergic nerve terminals in the nucleus accumbens so that a given dose of a
psychostimulant produces a greater increase in DA levels in the nucleus accumbens in
sensitized compared to non-sensitized individuals.
d. The three phases of cocaine abstinence are:
1. Crash—the user feels exhausted and suffers from a depressed mood
2. Withdrawal—lack of energy, anhedonia (inability to experience normal pleasures),
anxiety, and a growing craving for cocaine that increases the risk of relapse
3. Extinction—symptoms subside, although relapse may still occur
e. The negative mood state and craving associated with cocaine stem from temporary
decreases in synaptic levels of DA.
f. A single dose of cocaine may trigger a stroke or seizure. Chronic use can lead to
heart complications, including chest pain, cardiac arrhythmias, cardiac myopathy
(damaged heart muscle), and heart attack. Other organs, such as the lungs,
gastrointestinal tract, and kidneys may be damaged by cocaine. Frequent snorting may
lead to perforation of the nasal septum. Cocaine ingestion by a pregnant woman can
have profound effects on the unborn child, leading to attention deficit and other
cognitive-behavioral abnormalities. High doses can lead to panic attacks, delusions,
and hallucinations (e.g., “cocaine bugs” which create the sensation of something
crawling over the surface of one’s skin). Cocaine psychosis may occur.
g. Desipramine is a tricyclic antidepressant that inhibits NE uptake. It is used to treat
depression symptoms in patients recovering from cocaine abuse or dependence.
h. Cocaine abuse is associated with significant impairments in verbal memory, attention,
and motor function.
i. Psychosocial treatment programs involved individual, group or family counseling
designed to educate the user, promote behavioral change, and alleviate some of the
problems caused by the cocaine abuse. Cognitive behavior therapies are aimed at
restructuring cognitive processes and training the user either to avoid high-risk
situations or to employ appropriate coping mechanisms in such situations (relapse
prevention). Also available are 12-step programs such as Narcotics Anonymous or
Cocaine Anonymous.
j. Higgins et al developed a 24-week outpatient multi-component behavioral treatment
program based on the premise that drug taking is an operant response that persistes
mainly due to the reinforcing properties of the drug. By altering reinforcement
contingencies and increasing the availability of non-drug reinforcers, the program
promotes abstinence and helps the patient shift to a drug-free lifestyle. Each negative
urine test is reinforced by a voucher that can be redeemed for money, YMCA passes,
and educational materials. The program has community reinforcement elements that
are designed to help with social support, relationships, recreational activities and job
opportunities.
III-4
a. Common amphetamines include 1-amphetamine (Benzedrine), d-amphetamine
(Dexedrine), methamphetamine, MDMA, MDA, and MDE. The two naturally occurring
plant compounds similar in structure to amphetamine are cathinone (primary active
ingredient in khat) and ephedrine, found in the herb Ephedra vulgaris used in Chinese
medicine.
b. Ephedra sharply elevates blood pressure and increases the risk of heart attack or
stroke.
c. Methamphetamine is more potent than amphetamine in its effects on the central
nervous system.
d. Amphetamine and methamphetamine block the reuptake of catecholamines and also
trigger the release of catecholamines from nerve terminals. At very high doses, they
can also act as MAO inhibitors.
e. Amphetamine causes heightened alertness, increased confidence, feelings of
exhileration, reduced fatigue, and a generalized sense of well-being. It can improve
performance on simple, repetitive psychomotor tasks, as well as a delay in sleep onset,
a reduction in sleep time and in REM period duration. Amphetamine permits sustained
physical effort without rest or sleep and can enhance athletic performance. It is highly
reinforcing and has a few medical uses, such as in the treatment of narcolepsy and
ADHD. In high doses, it can produce a psychotic reaction consisting of hallucinations,
paranoia, delusions, and behavioral disorganization.
f. Administration of multiple doses of methamphetamine to animals causes long-lasting
reductions in the levels of DA, tyrosine hydroxylase, and DAT in the striatum,
suggesting damage to DA axons and terminals. It also produces damage to
serotonergic fibers in several parts of the brain, including the neocortex, hippocampus,
and striatum.
III-5
a. MDMA is considered an entactogen because of its ability to elicit a “touching within,”
or in more direct terms, and enhanced ability to introspect and to confront disturbing or
painful emotions.
b.MDMA produces mild euphoria, enhanced sensory perception, increased energy,
feelings of well-being and self-confidence, a desire to be with and interact with other
people, and sometimes sexual arousal. It can also increase heart rate, blood pressure,
body temperature, seating and salivation; and lead to tremors, and bruxism (tightening
of the jaw muscles).
c. MDMA differs from other amphetamines in that its primary mode of action is to
enhance the release of 5-HT and inhibit 5-HT reuptake. It also stimulates DA release,
but not as much as 5-HT.
d. Methylphenidate and other psychostimulants in low doses can have a calming effect
on individuals with ADHD. Striatal DAT density may be higher in individual with ADHD,
resulting in faster clearance of DA from the synaptic cleft. NE dysfunction has also
been implicated in ADHD.
e. Chronic MDMA exposure may cause pruning of serotonergic axons and terminals in
various forebrain areas such as the cortex and hippocampus. Although MDMA initially
stimulates serotonergic activity, it seems to damage serotonergic fibers in the long-term.
MDMA users have lower 5-HIAA levels in the CSF, a decreased density of the 5-HT
transporter, and diminished hormonal responses to pharmacological challenge of the
serotonergic system. There is some evidence of an association between heavy MDMA
use and cognitive deficits on neuropsychological tests—especially on memory tasks.
4/1/08- Review Session
II-9e Give a possible reason why reinforcement may occur.
The mesolimbic DA pathway has been shown to be linked to reinforcement for
psychomotor stimulants like cocaine and amphetamines.
Attention to novel stimuli tends to produce activation of this pathway. So, we might
theorize that the pathway may have to do with novelty-seeking behavior, which is
rewarding.
II-9d In progressive-ratio, first subjects are trained in an operant conditioning paradigm
using continuous reinforcement. Then the reinforcement schedule shifts from a
continuous to a fixed ratio schedule (e.g., a reward for every five responses). Then, the
ratio is increased (the number of responses to reward) until the subject stops engaging
in the behavior. That is the breaking point. The larger the ratio of the breaking point,
the greater the reinforcing properties of a drug.
II-2a
The preganglionic neurons of both the sympathetic and parasympathetic nervous
system ar cholinergic, as are the ganglionic neurons of the parasympathetic.
II-2
The regulation of movement in the nigrostriatal tract involves a balance betwen DA and
ACh. Too little DA results in too much ACh, and so anticholinergic drugs (orphenadrine,
benztropine, trihexylphenydyl) can be helpful in the early stages of Parkinson's, bringing
down ACh activity in order to boost DA.
II-1a
The rate of ACh synthesis is dependent on levels of choline and acetyl coA, which are
the precursors, as well as the firing rate of cholinergic neruons.
II-13a
Non-specific effects of alcohol are related to alcohol's ability to penetrate a membrane
and to change the structure of the phospholipids that make up the membrane, thus
affecting the membrane's function.
Specific effects: binding of ethanol to neurotransmitters, receptors, changing ion
channels, stimulating the release of G proteins (second messengers)
NEUROTRANSMITTER
RECEPTOR
AGONIST
ANTAGONIST
OTHER
Acetylcholine
Nicotinicionotropic,
open Na & Ca
channels,
located in symp.
& parasymp ns
succinylcholine
(muscle
relaxant)
D-tubocurarine
(curare) blocks
transmission at
neuromuscular
junction
AChE inhibitorsreversible:
neostigmine,
pyridostigmine;
irreversible:
Sarin and Soman
muscarinic-metabotropic,
located in
hippocampus,
thalamus,
striatum,
smooth muscle
muscarine,
pilocarbine,
arecoline
parasympathomimetic
(increase in
salivation,
sweating,
abdominal
pain)
atropine,
scopolamine
parasympatholytic-- inhibit
para ns activity
used for dilating
pupils; reduces
salivation during
surgery, produce
drowsiness
__________________________________________________________________________________
both-medulla,
pons (dorsal raphe),
midbrain
Serotonin
1A- hippocamp Buspirone:
agydala, septum reduces
metabotropic
anxiety
stimulates
appetite
2A-- cerebral
LSD
cortex striatum,
nucleus, accumbens
metabotropic
clozapine, risperidone
antipsychotic
__________________________________________________________________________________
ionotropic
MSG
PCP or
co-agonist
Glutamate
opens Na &
domoic acid
Ca channels
found in cortex,
projects to
striatum,
hippocampus, thalamus,
brainstem
LEARNING/
MEMORY
ketamine
(non-competitive)
D-serine
glycine
__________________________________________________________________________________
A- ionotropic
A- muscimol
Biculline
Tiagabinecortex, hippocampus,
(hallucino(produces
inhibits
substantia nigra,
genic)
convulsions)
GABA
GABA
striatum, cerebellum,
transporters
globus pallidus,
BDZs,
antiolfactory bulb
barbiturates,
seizure
B-metabotropic
& other CNS
depressants
Vigabatrininhibits the
enzyme that
breaks down
GABA
_________________________________________________________________________________
Opioids
metabotropic, open
K and close Ca
channels,
found throughout
the n.s.
opiates
(morphine,
naloxone
naltrexone
heroin,
methadone)
CH.10: Opiates
II-15
a) When taken orally, morphine and heroin are about equally potent, but heroin
becomes much more potent when injected, because it is more fat-soluble and moves
across the blood-brain barrier more readily.
b) When opiates bind to opioid receptors, they produce various CNS effects, including
pain relief, depressed respiration (slower and more shallow), pupil constriction,
drowsiness, impaired concentration, reduced awareness of the environment, reduced
anxiety, cough suppression, decreased appetite, lower body temp, reduced sex drive,
hormonal changes, nausea, vomiting and euphoria (or dysphoria in some cases). The
biggest effect on the gastrointestinal tract is constipation.
c) There are three opioid subtypes: mu, delta, and kappa. The mu-receptor is
distributed throughout the brain and spinal cord and play an important role in analgesia
(medial thalamus, spinal cord), reinforcement (nucleus accombens), and cardiovascular
and respiratory suppression (brain stem).
The delta-receptors are less widely distributed than mu-receptors, and are found mainly
in forebrain structures such as the neocortex, striatum, olfactory areas, substantia nigra
and nucleus accumbens. Delta-receptors have been implicated in modulating olfaction,
in reinforcement, motor integration, and cognitive function.
The kappa-receptors is found in the striatum and amygdale, but also in the
hypothalamus and pituitary, suggesting that they besides playing a role in regulation of
pain perception and mood, they have hormonal effects that influence, among other
things, water balance, feeding, and temperature control.
d) The endogenous opioids (also called endorphins) include: prodynorphin, POMC,
and proenkephalin. They are manufactured in the soma of neurons in the brain, spinal
cord, and autonomic nervous system, concentrated in areas related to mood and pain
modulation. POMC is found in high concentrations in the pituitary gland.
e) Opioid receptors are metabotropic and are linked to G proteins that tend to open
potassium channels and close calcium channels. By opening potassium channels,
endorphins hyperpolarize the cells. And by closing calcium channels, they block the
release of neurotransmitters (exocytosis). Endorphins can act by inhibiting the
postsynaptic neuron, activating autoreceptors that inhibit neurotransmitter release, or
inhibiting axoaxonic connections in a way that also inhibits neurotransmitter release.
YOU DO NOT NEED TO KNOW THE KEY TERMS “transfection” and “receptor
cloning.”
II-16
a) Early pain (or “first” pain) is the immediate sensory component and late pain (or
“second” pain) focuses more on the emotional component. A-delta fibers, which are
myelinated, transmit early pain, whereas the unmyelinated C fibers transmit late pain.
Early pain goes from the spinal cord to the thalamus and then to the somatosensory
cortex, whereas late pain goes from the spinal cord and thalamus to limbic structures
such as the hypothalamus and amygdale, as well as the anterior cingulate, which is
important in regulating emotion, attention, and motor responses.
b) Opiates regulate pain in three ways:
1. within the spinal cord by small inhibitory interneurons (that block transmission up the
spinal cord);
2. by two significant descending pathways originating in the periaqueductal gray, that
deliver an inhibitory signal down the spinal cord and thus prevent pain signals from
travelling up the spinal cord into the brain;
3. at many higher brain sites, such as the amygdala, thalamus and hypothalamus, thus
affecting somatosensory, emotional and hormonal aspects of pain response.
c) Directly by inhibiting spinal cord neurons or indirectly by sending an inhibitory signal
down the descending pathways.
d) The PAG is the starting point of two descending pathways associated with pain
regulation, one of which goes through the raphe nuclei and the other through the locus
coeruleus.
II-17
a) Opiates injected into the VTA increase the firing of dopaminergic neurons, probably
by inhibiting GABA cells in the VTA that would otherwise inhibit dopaminergic neurons.
Kappa-agonists tend to have the opposite effect on dopaminergic neurons, inhibiting
their firing rate.
b) 1. Tolerance—The effects of opiates diminish rapidly, especially the analgesic and
euphoric effects. 2. Sensitization—In some cases, the effects of the opiates increase
with repeated administration; this is true for craving. 3) Physical dependence—
Abstinence from opiates after continued use produces withdrawal effects that tend to
involve hyperactivity. Although withdrawal symptoms are generally not life-threatening,
they can be very unpleasant
c) Pain, dysphoria, hyperactivity, restlessness, anxiety, flu-like symptoms (see Table
10.2).
d) It is unusual to see addictive behavior in chronic pain patients, although they do show
tolerance and can also experience withdrawal symptoms.
e) The PAG and locus coeruleus are implicated in opiate withdrawal.
f) Himmelsbach (1943) suggested that acute morphine administration disrupts the
organism’s homeostrasis, but repeated administration of the drug initiates a mechanism
that compensates for the original effects and returns the organism to homeostasis. This
hypothesis is precursor of opponent-process theory.
g) The acute effects of opioids on mu-receptors is hyperpolarization and a reduced firing
rate; chronic administration produces a gradual increase in both, as tolerance develops.
During opioid withdrawal, the firing rate rises to pre-treatment levels.
h) Tolerance—Environmental cues paired with drug administration produce an
anticipatory physiological response, because the tolerance to the drug that occurs with
repeated use becomes associated with those cues. Abuse—Drug cravings become
associated with environmental cues such as needles, which increase metabolic activity
in brain areas such as the amygdale and anterior cingulate. Relapse—Withdrawal
symptoms such as increased body temperature and restlessness can be conditioned to
environmental cues. This increases the likelihood of relapse in familiar settings.
II-18
a) Biopsychosocial models of therapy address:
1. The physiological effects of the drug on the nervous system.
2. The psychological status of the individual and his/her unique neurochemical makeup
and history of drug use.
3. The environmental factors that provide salient cues for drug taking and powerful
secondary reinforcement.
b) Methadone is an opiate that eases withdrawal symptoms. Clonidine is an adrenergic
agonist that inhibits norepinephrine activity triggered by opiate withdrawals and thus
reduces symptoms such as chils, sweating and muscle aches.
c) Methadone maintenance is the long-term substitution of one opiate for another. The
rationale is that the relief of cravings reduces dangerous drug-seeking behavior.
Eventually, the patient is weaned from methadone. The percentage of patients who
remain abstinent 1-3 years after methadone withdrawal is estimated to be as high as
80% (and 40% after six years), compared to 12% of patients who drop out of
methadone maintenance programs. They also show lower rates of criminal activity, HIV
infection, and mortality.
d) Methadone was chosen for use in opiate drug treatment programs for the following
reasons:
1. Because of cross-dependence with heroin, methadone can prevent withdrawal
symptoms associated with abstinence from those drugs.
2. Because of cross-tolerance, taking methadone reduces the euphoric effects of
heroin.
3. Oral administration of methadone produces little euphoria or craving and reduces the
risks associated with needle use.
4. Methadone is relatively long-lasting, which produces fewer extremes in terms of the
drug effects.
5. Methadone is considered medically safe even with long-term use and does not
interfere with daily activities.
e) LAAM and buprenorphine (Buprenex) are longer-lasting than methadone and
produce even more stable pharmacological effects, including milder withdrawal
symptoms, and require less frequent administration.
f) Narcotic antagonists such as naltrexone have limited usefulness because the use of
these drugs requires an addict to willingly substitute an antagonist (that blocks opiate
receptors) for a drug with highly reinforcing properties. Antagonists do not elminate
craving, and so addicts who are less motivated stop taking these drugs. Only 10% of
addicts choose to take part in antagonist treatment programs, and only 27% of these
individuals complete a 12-week program.
*multidimensional approach—includes a combination of detox, pharmacological
support, and group/individual counseling, as well as job training, educational counseling
and family therapy, in some cases
3/13/08PLEASE NOTE: THE STRUCTURE OF OUR CLASS MEETINGS WILL BE
DIFFERENT THE REST OF THE SEMESTER. INSTEAD OF FORMAL LECTURES,
WE WILL BE HAVING INFORMAL DISCUSSIONS OF THE MATERIAL AND I WILL BE
ANSWERING YOUR QUESTIONS. I WILL POST NOTES PRIOR TO CLASS. THE
BEST STRATEGY IS TO DO THE ASSIGNED READINGS AND LOOK OVER THE
LECTURE NOTES BEFORE CLASS. THAT WAY, YOU CAN DECIDE WHICH
TOPICS YOU WOULD LIKE TO COVER IN MORE DETAIL.
Alcohol is most commonly produced through fermentation of sugars by yeast. Once the
concentration reaches 15%, the yeast die off. Distillation is used to increase the
concentration, up to 95.6% (alcohol is an azeotrope).
How does alcohol interact with different neurotransmitter systems:
1. Glutamate-- Alcohol acts as an antagonist at NMDA receptors; this inhibits memory
and learning. One possible mechanism is that alcohol binds directly to glutamate in a
way that prevents it from binding to the receptor. Chronic alcohol use is going to result
in up-regulation of NMDA receptors, which can lead to excitotoxicity during abstinence.
This can account for certain alcohol withdrawal effects such as tremors and seizures.
2. GABA-- Alcohol enhances GABA activity at GABA-A receptors by binding to
modulatory sites on the receptor. Chronic alcohol use leads to down-regulation of
GABA-A receptors. This too can explain some of the symptoms of withdrawal such as
seizures, tremors, and hyperexcitability.
3. Dopamine- Alcohol does stimulate dopaminergic neurons associated with the
mesolimbic pathway, which is the brain's reward pathway. It acts as an agonist,
increasing the firing rate of dopaminergic neurons in the VTA. That causes increased
DA levels in the nucleus accumbens (NA).
NA is connected to: a) the amydala-- emotion and motivation; and b) the striatum-motor activity.
Chronic alcohol use results in down-regulation of DA neurons in the mesolimbic tract.
4. Opioids- Alcohol enhances opioid actvity by increasing the release of endogenous
opioids (endorphins, enkephalins) and by stimulating gene expression of these opioids.
Chronic alcohol use reduces the gene expression (similar to down-regulation) and leads
to lower endorphin levels.
Blocking opioid receptors with antagonists such as naloxone and naltrexone reduces
alcohol self-administration in animals. Naltrexone is used as a pharmacotherapeutic
treatment for alcohol dependence.
3/11/081970- Comprehensive Drug Abuse Prevention and Control Act (Controlled Substance
Act) established five schedules of controlled substances (Schedule I drugs have no
accepted medical use and high abuse potential; Schedule V drugs have important
medical uses (cough suppressants) and low abuse potential).
What is addiction? The term "addiction" has many connotations and so the DSM has
replaced with the terms "substance dependence" and "substance abuse"). Substance
dependence is characterized by tolerance (more use has less effect), withdrawal
(unpleasant symptoms associated with drug abstinence), and craving (uncontrollable
desire for the drug).
Substance abuse is more a pattern of behavior that has negative repercussions in the
life of the user and of people in the user's life.
Modern conceptions of addiction focus on these qualities:
1. Compulsive drug-seeking and drug-taking behavior
2. Its relapsing nature
3. Its persistence in spite of harmful consequences
Continuum of drug use-- Patterns of drug use, abuse and dependence are individual. It
is hard to come up with a consistent pattern that applies to all addicts.
Five categories of abuse potential:
1. withdrawal symptoms
2. strength of the drug's reinforcing properties (how much does taking the drug increase
frequency of drug-seeking and drug-taking behavior).
3. Degree of tolerance
4. Degree of dependence based on difficulty quitting, relapse rate, and percentage of
users who become dependent
5. Degree of intoxication produced
1= most serious
6= least serious
The most problematic drug is heroin (1.9), followed by alcohol (2.5), cocaine (2.6), and
nicotine (3.35). The least problematic are caffeine (5.0) and marijuana (5.4). There is
not a correlation between the abuse potential of a drug and its schedule based on the
controlled substance act.
Models of addiction
Physical dependence model-- The addicted individual uses the drug to relieve
withdrawal symptoms. So drug-taking behavior is a form of negative reinforcement
(when a behavior stops an unpleasant stimulus).
Punishment-- negative stimulus is applied to decrease the frequency of an undesired
behavior
Negative reinforcement-- negative stimulus is removed when the desired behavior
occurs.
Criticisms of this model: 1) Some drugs, like cocaine, don't produce strong withdrawal
symptoms and yet have serious addiction potential; 2) The model does not explain how
dependence happens; 3) it has problems explaining the relapse of adicts who have
undergone detox.
Positive reinforcement model-- Using the drug reinforces drug-seeking behavior
We can measure the reinforcing nature of a drug using the progressive-ratio procedure,
increasing the ratio of behaviors to drug deliver (reward) until the subject reaches the
"breaking point" in which they don't engage in the behavior. The more reinforcing a
drug is, the higher the breaking point in terms of the reinforcement ratio.
Limitations of the the positive reinvorcement model are: 1) greater drug craving is often
accompanied by greater drug tolerance; 2) it doesn't explain why the negative
consequences of using the drug don't counteract the positive reinforcement (advocates
of this model argue that the time-frame makes a difference--that short-term
consequence are more reinforcing than long-term ones); 3) it doesn't account for
individual differences.
Incentive-sensitization model-- The neural systems involved in reinforcement ("liking")
and craving ("wanting") are different. Repeated use of an addictive drug sensitives the
wanting system but not the liking system.
Opponent-process model-- Neural mechanism that produces a certain affective
response (a-process) triggers an opposite response (b-process). The a-process has an
earlier onset and offset than the b-process, and it does not increase with repeated drug
use whereas the b-process does.
Koob & LeMoal (1997)-- Proposed a variation of opponent-process theory in which the
change that occurs with respect to repeated drug use is not an increase in the intensity
of the b-process but a change in the "hedonic set point" (the amount of response that
feels good).
Disease models-- are of two types:
1. Susceptibility models-- there is an inherited susceptibility to addiction
2. Exposure models-- Chronic drug use changes the brain in a way that leads to the
pattern of behavior and symptoms associated with addiction.
The susceptibility model promotes complete abstinence for addicts whereas the
exposure model does not.
Three personality-related pathways to addiction:
1. Behavioral disinhibition-- Some personality types, that are prone to impulsive,
antisocial, unconventional, and even aggressive behavior, with low levels of selfrestraint and harm avoidance, are more prone to abuse certain drugs.
2. Stress reduction-- Individuals who are high on traits such as stress reactivity,
anxiety, and neuroticism, are more likely to be drawn to drug use as a way of dealing
with negative emotions.
3. Reward sensitivity-- Sensation-seeking, extraverted, and who seeks drugs for their
positive reinforcing qualities.
3/6/08The lecture notes below were posted prior to class because Dr. Shamas is sick today
and will not be lecturing on this material. If you have any questions about the
information in these notes, please ask them during the review session on April 1.
II-7
a) The two major inhibitor amino acid neurotransmitters are GABA (gammaaminobutyric acid) and glycine.
b) GABA is synthesized from glutamate in a one-step process catalyzed by glutamic
acid decarboxylase, which removes a carbon dioxide molecule from glutamate.
c) Tiagabine inhibits the GABA transporter, GAT-1. This inhibition increases GABA
activity at the synapse, which in turn inhibits seizure activity. And so tiagabine is used
in the treatment of epilepsy.
Vigabatrin inhibits the enzyme GABA aminotransferase (GABA-T) that catalyzes one of
the steps in the breakdown of GABA. This increases GABA in the brain, which has an
anticonvulsant effect. And so vigabatrin has become the primary form of treatment for
certain forms of epilepsy.
d) GABA is widely distributed in the brain and can be found in the following areas:
cerebral cortex, hippocampus, substantia nigra, cerebellum, striatum, globus pallidus,
and olfactory bulb.
e) GABAA receptors are ionotropic; they open up chloride channels that hyperpolarize
the neuron. GABAB receptors are metabotropic.
f) Muscimol, which is found in the mushroom Amanita muscaria, is a GABAA agonist. It
produces hallucinations, hyperthermia, pupil dilation, elevation of mood, difficulties in
concentration, loss of appetite, ataxia, and catalepsy.
Bicuculline is a competitive GABAA antagonist that blocks the binding of GABA to the
receptor and therefore produces convulsions.
g) Benzodiazepines (BDZs) and barbiturates are agonists that bind to a site on the
GABAA receptor other than the GABA binding site. They do not open up ion channels
on their own but increase the efficacy of GABA (i.e., the ability of the neurotransmitter to
open ion channels in the receptor).


Benzodiazepines and barbiturates are two classs of CNS depressants that
enhance GABAA receptor activity.
Inverse agonists are substances that activate a receptor but produce the
opposite effect of a typical agonist at that receptor.
3/4/08GlutamateImportant excitatory neurotransmitter, with ionotropic receptors that produce very fast
postsynaptic responses. In the cortex, glutamate is used by the pyramidal cells that are
the major output neurons of the cortex, projecting to the striatum, limbic system
(hippocampus), thalamus, hypothalamus, and brainstem. It's important for learning,
memory and synaptic plasticity.
Unlike other neurotransmitters, glutamate plays a significant role in protein synthesis
and cell metabolism, and so all neurons and glial cells have it, not just glutamatergic
neurons.
Synthesis-- glutamate is made from glucose via the intermediate, glutamine, using the
enzyme glutaminase as a catalyst. Glutaminase remoses an amine group from
glutamine.
Release-- Three vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3)
package glutamate into the vesicles, where it's released into the synaptic cleft.
Transport- transporters EEAT1-EEAT5 (excitatory amino acid transporters) are
involved in the reuptake of glutamate and aspartate from the synapse.
Amyotrophic lateral sclerosis (ALS)-- Lou Gehrig's disease ("Pride of the Yankees), is a
neurological disorder in which motor neurons in the spinal cord and cortex degenerate.
The disease is correlated with abnormilities in EAAT2, suggesting that two much
glutamate is damaging neurons in people with ALS--particularly motor neurons in the
striatum.
There are three subtypes of glutamate receptors, each named for a specific agonist:
1. AMPA receptors (AMPA is a synthetic amino acid) -- these receptors produce the
fastest excitatory responses; they open sodium channels in the postsynaptic neuron.
2. Kainate receptors (kainic acid is derived from seaweed)-- also opens sodium
channels.
3. NMDA receptors (NMDA is a synthetic amino acid)-- open sodium and calcium
channels, and the calcium can act as a second messenger in the postsynaptic neuron
(even the receptor is ionotropic, it has some metabotropic mechanisms).
NMDA receptors are unique because they require a second neurotransmitter (either
glycine or D-serine) and not just glutamate to open their ion channels.
Glycine or serine are considered "co-agonists", meaning that they must bind to the
receptor simultaneously to open ion channels.
Four binding sites on NMDA receptors:
1. Glutamate
2. Glycine/Serine
3. Magnesium-- This site block the ion channel, and an action potential is needed to
dislodge the magnesium
4. Site that binds to PCP or ketamine; both drugs are non-competitive antagonists that
block the ion channels of NMDA receptors.
Evidence that NMDA receptors are important in learning:
1. Treatment of animals with NMDA receptor antagonists lead to learning impairments,
especially on spatial learning tasks (hippocampus has a high density of NMDA
receptors)
2. NMDA receptors are involved in long-term potentiation (LTP), which is hypothesized
to be involved in learning.
LTP is a persistent (more than 1 hour) increase the sensitivity of postsynaptic receptors
as a result of stimulating the presynaptic neuron.
3. Genetic strains of mice that have more efficient NMDA receptors show improvement
on spatial learning tasks and improved rate of learning fear responses.
Monosodium glutamate (MSG) produces brain damage and retinal damage in mice, as
well as hormonal problems (stunted growth, obesity, and reproductive problems) due to
damage to a part of the hypothalamus called the arcuate nucleus.
Excitotoxicity theory-- Too much glutamate keeps the neurons depolarized in a way
that damages or kills them. Evidence: injecting glutamate into a brain area of an adult
animal lesions that area).
NMDA receptors and excessive glutamate are implicated in:
1. necrosis-- cell death by lysis (bursting/splitting of the cell), which can happen after
continuous stimulation of both NMDA and non-NMDA glutamatergic receptors for
several hours.
2. apoptosis (programmed cell death)-- occurs in fetal development; it happens more
slowly and doesn't involve lysis. The cell's nucleus and DNA break up, and then the
whole mess is cleared by phagocytes. This is a normal development process that
improves the efficiency of the nervous system.
3. ischemia-- interruption of blood flow in the brain, which can be caused by a stroke
(localized) or heart attack (global). The result is a massive release of glutamate, which
leads to prolonged NMDA receptor activity. In the long term, this activity is extremely
damaging to the affected areas.
One treatment for ischemia that has been tried successfully in animals involves using
NMDA receptor antagonist tol slow down activation of NMDA receptors. Although this
works great in animals, it produces symptoms of psychosis in humans. A more effective
treatment is use antagonists that block the glycine/serine binding sites on the receptor.
This blocks the ion channel but doesn't seem to have as many negative side effects.
Domoic acid-- an excitatory amino acid that produces excitoxicity. The toxin is found in
relatively small concentrations in algae, in higher concentrations in filter feeders such as
clams or mussels that eat algae, and in even higher concentrations in people and
animals that eat the shellfish (bioaccumulation)
Victims develop the following symptoms: headache, dizziness, muscle weakness,
confusion, and permanent loss of short-term memory. In some cases, it's lethal.
2/28/08One last note about ACh: The regulation of movement involves the balance between
DA and ACh. Too little DA results in too much ACh, which results in overstimulation of
muscle cells. Many symptoms of Parkinson's are actually related to overstimulation of
muscle by ACh. In the early stages of Parkinson's, anticholinergic drugs are used to
treat some of those symptoms.
Orphenadrine, benztropine, trihexylphenidyl are all used to treat early Parkinson's and
are all competitive ACh receptor antagonists.
SEROTONIN
Serotonin (5-HT; 5-hydroxytryptamine) is involved in food intake, reproductive behavior,
mood, pain sensitivity, learning memory
5-HT is synthesized in a two-step process (Fig. 6-13)
5-HT levels can be affected by diet. Tryptophan competes with other amino acids to
corss the blood-brain barrier, and the rate with which it crosses depends on the ratio of
tryptophan to other amino acids in the bloodstream.
A diet high in protein decreases the ratio of tryptophan to other amino acids because of
all the amino acids contained in the protein.
But a diet low in protein and high in carbohydrate increase this ratio: It stimulates
insulin release, which helps in the uptake of most amino acids from the bloodstream,
but NOT tryptophan. So, more tryptophan stays in the bloodstream relative to other
amino acids and is more likely to cross the blood-brain barrier.
There are similarities and differences between 5-HT and the catecholamines:
1. Similarities
a. Serotonin is transported into the vesicles by the same vecisular transporter proteins
as DA and NE.
b. The storage of serotin in vesicles protects it from enzymatic breakdown in the same
way that it does DA and NE, and so VMAT (vesicular transporter for monoamines)
blockers like reserpine that deplete DA and NE also deplete 5-HT.
c. Serotonergic autoreceptors are similar to the ones for DA and NE. The ones on the
axon reduce the rate of exocytosis, and the ones on the soma and dendrites inhibit cell
firing.
d. The reuptake of 5-HT is similar to that of DA and NE, even though it involves a
different transporter.
e. Certain abused drugs such as cocaine and MDMA interact with the transporters for
both 5-HT the catecholamines.
f. 5-HT is broken down by MAO, as are DA and NE
2. Differences
1. Drugs like fenfluoramine that stimulate the release of 5-HT specifically but not of DA
or NE.
2. It has its own transporter (5-HT transporter)
3. This transporter can be attacked specifically by a class of drugs that do not attack
the transporters for DA and NE. This class of drugs is called selective serotonin
reuptake inhibitors (SSRIs), which includes Prozac (fluoxetine).
4. 5-HT is not affected by the enzyme COMT, which only breaks down catecholamines.
5-hyroxyindoleacetic acid (5-HIAA) is the by-produce of 5-HT breakdown by MAO; it is
measured as an indicator of serotonergic activity in the nervous system. More activity
means higher levels of 5-HIAA.
Where are serotonergic neurons found?
Medulla, pons, and midbrain is where the vast majority of cell bodies are found.
Most of the serotonergic fibers in the forebrain originate in the dorsal and median raphe
nuclei.
Serotonergic neurons isn the dorsal raphe are activated during movement and inhibited
when an animal is attending to stimuli in the environment; these cells are also inhibited
during REM sleep, when the muscles of the body are essentially paralyzed. This
suggests that the 5-HT cells in the dorsal raphe facilitate motor activity and suppress
sensory activity.
15 types of 5-HT receptors. The best known subtypes are 5-HT1A and 5-HT2A.
5-HT1A receptors are found in several brain areas, including the hippocampus,
amygdala, septum, and raphe nuclei. They are metatropic and work by two
mechanisms:
1. Reduce the synthesis of cAMP by blocking adenylyl cyclase. This in turn reduces
the amount of protein kinases, which phosphorylate different kinds of proteins in the
neuron.
2. Increase the opening of potassium channels, which hyperpolarize the membrane.
5-HT1A receptor agonists result in overeating (hyperphagia), which is caused by
stimulating 5-HT autoreceptors, and thus inhibiting serotonin release. They can reduce
anxiety (buspirone). They can reduce alcohol consumption in rats. And they can cause
hypothermia.
5-HT2A receptors are also found in several brain areas, including the cerebral cortex,
striatum and nucleus accumbens.
5-HT2A receptor agonists are hallucinogens in humans (example: LSD)
5-HT2A receptor antagonists are sometimes used as antipsychotic drugs. Examples:
clozapine and risperidone. They block 5-HT2A receptors as well as D2 dopaminergic
receptors. These drugs seem to reduce movement-related side effects produced by
other antipsychotic drugs such as haloperidol, which is a dopamine antagonist.
2/26/08Announcements: Grades are now posted online under "413Grades." The grade cutoffs
are:
A
B
C
D
25-30
20-24
15-19
10-14
Question #4 was thrown out and a point was awarded to EVERYONE.
CH.6: Acetylcholine
Acetylcholine is made in a single step from choline (derived from fats) and acetyl
coenzyme A (acetyl CoA), a reaction that is catalyzed by choline acetyltransferase.
This enzyme transfers an acetyl group from the coenzyme to the choline.
Neurons that produce acetylcholine (ACh) as a neurotransmitter are called cholinergic
neurons. These neurons make more ACh when there is more choline and acetyl coA
available and when the neurons are firing at a more rapid rate.
Drug Effects on Cholinergic neurons:
1. Interfering with Vesicular Transport
Vesamicol blocks the vesicular ACh transporter protein that loads ACh into the vesicles.
This decreases ACh levels in the vesicles but increases those levels in the cytoplasm.
It also decrease the rate with which ACh is released into the synapse.
2. Interfering with the Breakdown of ACh
The enzyme acetylcholinesterase (AChE) breaks down ACh into choline and acetic
acid. This enzyme is found in:
a. Presynaptic neurons-- where it breaks down excess ACh
b. Postsynaptic neurons-- on the membrane, where it breaks down ACh after it's
released into the synapse and has bound to a cholinergic receptor.
c. Neuromuscular junction-- where ACH is broken down after a muscle contraction so
that the muscle can relax.
AChE inhibitors fall into two classes: reversible and irreversible. Reversible AChE
inhibitors have a short-term effect on the enzyme by binding to it. Irreversible inhibitors
can damage or neutralize the enzyme.
Reversible AChE inhibitors:
i. physostigmine-- naturally-occurring plant extract that was used in West Africa as a
form of punishment for those accused of a crime. It crosses the blood-brain barrier and
results in stimulation of cholinergic receptors in the CNS. Symptoms include slurred
speech, confusion, hallucinations, loss of reflexes, convulsions, and possibly coma and
death.
(Other symptoms that can occur with the overstimulation of choinergic neurons include
chest and abdominal pain, nausea, vomiting, sweating, and salivation)
ii. Synthetic analogs of physostigmine (neostigmine and pyridostigmine) that do not
cross the blood-brain barrier. They are used in treating myesthenia gravis, an
autoimmune disorder that attacks cholinergic receptors at neuromuscular junctions. By
inhibiting AChE, they keep ACh active longer at ther neuromuscular junction, which
helps to stimulate the undamaged receptors.
Irreversible AChE inhibitors: These are used as insecticides in their weak enough and
as nerves gas in their strong from (Sarin, Soman). Symptoms of nerve gas poisoning
include vomiting, convulsions, profuse sweating and salivation, gasping for breath.
The antidote for these nerve gases are reversible AChE inhibitors, such as
pyridostimine. The temporary inhibition of AChE by a reversible inhibitor protects the
enzyme against permanent inactivation by the nerve gas. But the antidote must be
taken BEFORE exposure to the nerve gas.
Pyridostigmine when taken over a course of weeks or months may have side effects
such as cognitive impairment, dizziness, and problems of balance and coordination.
These are symptoms reported by veterans diagnosed with Gulf War Syndrome.
Which neurons in the brain are cholinergic neurons? The preganglionic neurons of both
the sympathetic and parasympathetic nervous system produce ACh. So do the
ganglionic neurons of the paraysmpathetic nervous system. The parasympathetic
nervous system is made up entirely of cholinergic neurons and the sympathetic nervous
system is made up partially by cholinergic neurons, which are found only in the portion
of those pathways lying within the CNS.
The cell bodies of cholinergic neurons are found primarily in two brain areas: the
midbrain and the basal forebrain.
The basal forebrain cholinergic system (BFCS) has been implicated in cognitive
functioning. Rats with damage to this system show impairments in memory, attention,
and learning.
There are two types of cholinergic receptors in the nervous system and on muscle cells:
a. nicotinic receptors-- respond to nicotine as an agonist
b. muscarinic receptors-- respond to muscarine as an agonist. Muscarine is an alkaloid
(a nitrogen-containing compound) that is found in the fly agaric mushroom, Amanita
muscaria.
3. Drugs can act as nicotinic agonists or antagonists
Nicotinic receptors are highly concentrated on muscle cells at neuromuscular junctions,
on ganglionic cells of both the sympathetic and parasympathetic nervous system, and in
certain brain areas. They are ionotropic receptors that open up sodium and calcium
channels. If they open up sodium channels, they cause deparization of the membrane,
and if they open up calcium channels, they stimulate release of the neurotransmitter
(exocytosis).
Nicotinic receptor agonist-- Succinylcholine produces continuous depolarization of the
membrane that eventually results in "depolarization block," in which the resting potential
of the neuron cannot be re-established and so the neuron cannot fire again. It is used
as a powerful muscle relaxant during surgery. Because muscles of the diaphragm are
paralyzed, the patient must be maintained on a ventilator until the drug wears off.
Nicotinic receptor antagonis-- D-tubocurarine, the active ingredient in curare, is a poison
that indigenous tribes of South America use on their arrowheads. It has a high affinity
for nicotinic receptors and blocks the neuromuscular junction. In high enough doses, it
causes respiratory paralysis that results in death.
4. Muscarinic receptor agonists and antagonists
Muscarinic receptors are widely distributed in the brain (neocortex, hippocampus,
thalamus, striatum, and basal forebrain). They are metabotropic receptors and have a
variety of effects. In the neocortex and thalamus, they serve a cognitive function; in the
striatum, a motor function. They are also linked to the reward system of the brain.
These receptors are also found outside the brain in cardiac muscle and the smooth
muscle of internal organs such as the stomach and intestines. They are involved in
parasympathetic activation, which slows heart rate and the strength of contraction of the
heart beat, and activates secretions such as saliva, sweat, and tears.
Muscarinic receptor agonists-- These drugs (muscarine, arecoline) are
parasympathomimetic agents, which means that they mimic the effects of
parasympathetic activation. They can lead to excessive production of tears, saliva, and
sweat; pupil constriction, abdominal pain, strong contractions of visceral muscles,
diarrhea, and convulsions.
Muscarinic receptor antagonists-- These drugs are parasympatholytic agents (atropine
and scopolamine, which are both naturally occurring alkaloids) inhibit the
paraysmpathetic nervous system. Atropine is used to dilate pupils and can also be
used in surgery to reduce secretions such as saliva that can block airways. Also used
to counteract poisoining by cholinergic agonists. Scopolamine produces drowsiness,
euphoria, amnesia, fatigue, and dreamless sleep. Also used to treat seasickness by
counteracting the effects of nausea.
2/19/08- Review Session
Midterm 1 this Thursday. Punctuality and attendance count!!!!!
Weak acids ionize better in basic (or alkaline) solutions, and weak bases ionize better in
acidic solutions.
I-16b.
L-DOPA is a precursor to dopamine and so it's given to patients with Parkinson's
disease to try to increase dopamine levels in the CNS
AMPT (alpha-methyl-para-tyrosine) blocks tyrosine hydroxylase (rate-limiting enzyme in
the synthesis of catecholamines), thus interfering with catecholamine synthesis; it has
no therapeutic value but is used in research to simulate conditions in which there are
low levels of catecholamines in the brain.
I-17d
DA receptor agonist-- stimulates or activates behavior
DA receptor antagonist-- suppress certain kinds of behavior, can produce catalepsy
(lack of spontaneous movement); D2 antagonists (e.g., haloperidol) have been used to
treat schizoprhenia.
I-7 key terms
convergence-- several axon terminals synapse onto a single neuron
divergence-- several axon terminals from the same neuron synapse onto several other
neurons
I-8
a) At rest, there are several forces at play in the neuron:
1. Concentration gradient-- the tendency for substances to go from areas of higher
concentration to lower concentration: For sodium, the conc grad is driving the ions into
the cell, and for potassium, it's driving them out.
2. Electrical gradient (electrostatic potential) -- The tendency of charged particles to go
towards the opposite charge. At rest, the potential is -70mV (more negative inside the
neuron), which is going to drive both sodium and potassium into the cell.
3. Potassium channels are not gated whereas sodium channels are (voltage-gated)
4. Sodium-potassium pump-- a protein in the cell membrane that exchanges sodium for
potassium; for every three sodium ions that are "pumped" out of the neuron, two
potassium ions are pumped in.
d) Action potential:
1. The potential increases (depolarization) until it reaches -50mV, which is the
threshold potential.
2. When this potential is reached, the sodium channel opens.
3. The voltage rapidly increases to +40mV, and then the sodium channel closes.
4. Meanwhile, potassium has been flowing out of the neuron because it is driven
outward by both electrical and concentration gradients.
5. Sodium-potassium pump restores the potential back to -70mV by pumping out
sodium and pumping in potassium in a 3/2 ratio.
EPSP and IPSP-- excitatory postsynaptic potential, which is produced by opening
sodium channels and depolarizing the cell; the inhibitory postsynaptic potential, which is
produced by opening chloride channels and hyperpolarizing the cell.
Volume transmission-- diffusion of a chemical signal through the extracellular fluid to
reach target cells at a distance from the point of release. In general, neurotransmitters
move across a synapse to an adjacent neuron, but they can travel longer distances to
other neurons that do not synapse with the neuron producing the neurotransmitter.
I-17e
6-Hydroxydopamine (6-OHDA) is a neurotoxin that kills dopaminergic cells; haloperidol
is a DA receptor antagonist, which blocks the binding of DA to its receptors. The effect
of 6-OHDA is to lower DA levels in the brain.The effect of haloperidol is NOT to reduce
DA levels but to reduce the rate of binding of DA to receptors. BOTH result in upregulation, which is an increase in the number of receptors, although the increase
happens for different reasons in each case. In the case of 6-OHDA, up-regulation
happens to compensate for lower DA levels, and in the case of haloperidol, it happens
to compensate for lower binding rates.
I-16g
tricyclic antidepressants-- inhibit the reuptake of NE and serotonin
Reboxetine-- just inhibits or blocks the reuptake of NE
cocaine- inhibits the reuptake of DA, NE, and serotonin
The way a drug blocks reuptake is by binding to the transporter
Cocaine has a high level of affinity for the transporter (it binds well to it).
The term "efficacy" is used to refer to a drug or neurotransmitter's ability to exert an
effect once it binds to a receptor.
2/14/08Midterm 1 Next Thursday covers Unit 1 (Lessons I-1 through I-18), which corresponds
to CHs 1, 2, 3, and 5.
Behavioral supersensitivity-- If an animal is given a dopamine antagonist such as
haloperidol for an extended period of time and then the treatment is stopped. When the
animal is then given a dopamine agonist (e.g., apomorphine), that animal is going to
respond much more strongly to the agonist than a control animal.
NOREPINEPHRINE
Locus coeruleus-- Found in the pons; it is the primary source of norepinephrinecontaining neurons (noradranergic neurons); provides nearly all of the NE in the cortex,
limbic system, thalamus, hypothalamus, cerebellum, and spinal cord.
Norepinephrine is both a neurotransmitter and a hormone. NE can reach the heart by:
1. Being released from sympathetic noradrenergic neurons that are connect to the
muscle tissue of the heart at a neuromuscular junction. (NE acting as a
neurotransmitter)
2. Being released from the adrenal glands and traveling through the circulatory system
to the heart . (NE acting as a hormone)
Behavioral effects of NE: its effects can be related to triggering hunger and eating
behavior; sexual behavior; fear and anxiety; pain; sleep and arousal; vigilance.
Four types of adrenoreceptors: alpha1, alpha2, beta1, and beta2
Alpha receptors- act like D2 receptors, inhibiting adenylyl cyclase and thus reducing the
rate of synthesis of cAMP.
Beta receptors-- stimulate adenylyl cyclase and thus enhance the synthesis of cAMP
Adrenergic agonistsUsed in the treatment of bronchial asthma (e.g., albuterol is a beta adrenergic
agonist); these agonists constrict blood vessels in the bronchial lining and thus reduce
congestion and fluid buildup in the lungs.
Neosynephrine contains phenylephrine, which is an alpha-receptor agonist. It constricts
blood vessels in the nose and reduces inflammation of nasal membranes; the same
ingredient is found in certain eye drops because it also dilates the pupils.
The simple version of the story is that NE agonists increase sympathetic response. The
exception to this is alpha2 agonists such as clonidine, which actually inhibit sympathetic
nervous system activity.
Adrenergic antagonists"Beta blockers" are beta antagonists such as propanolol, metoprolol they're useful in
treating hypertension because they dilate the blood vessels. Just as an NE agonist
would, in general, result in sympathetic arousal, an NE antagonist would stimulate the
parasympathetic NS or suppress sympathetic arousal. One symptom of that arousal
would be constriction of blood vessels, and these antagonists do the opposite, causing
dilation.
They're also used to treat cardiac arrhythmia (irregular heartbeat) and angina pectoris
(chest pain). They've also been used to treat the symptoms of generalized anxiety
disorder such as tachycardia (racing heart).
Alpha antagonists have been used in the treatment of sexual impotence, by increasing
parasympathetic activity.
2/12/08Next Tues: Review session-- Bring questions if you have them.
Next Thurs: First midterm. Don't be late and don't be absent.
CH.5: Catecholamines
Catecholamines are a class of neurotransmitters that includes dopamine (DA) and
norepinephrine (NE). Although epinephrine is a catecholamine, it's not included in this
discussion because it is not a neurotransmitter.
The mechanism by which the brain produces catecholamines is shown in Fig 5.2.
L-DOPA is used therapeutically to increase catecholamine formation. It's used in the
treatment of Parkinson's
alpha-methyl-para-tyrosine (AMPT)-- blocks tyrosine hydroxylase, and so it interferes
with catecholamine synthesis; it doesn't have a therapeutic use but it is used in research
Nomenclature
Dopaminergic-- neuron or a pathway that involves dopamine (DA)
Noradrenergic-- neruon or pathway that involves norepinephrine (NE)
Like most neurotransmitters, catecholamines are packaged in vesicles. This packaging
has two important functions:
1. It delivers a "pre-measured" amount of the neurotransmitter into the synapse.
2. It protects the neurotransmitters from getting broken down by enzymes in the axon
terminal.
The effects of certain drugs on catecholamines:
1. Reserpine-- Used in the treatment of high blood pressure; can act as a sedative and
depressant. Blocks vesicular monoamine transporters (VMAT), which are proteins that
draw the monoamine neurotransmitters into the vesicle. Monoamines include serotonin
as well as the catecholamines.
2. Amphetamine and methamphetamine-- Cause exocytosis--the breaking of vesicle
and the release of catecholamines into the synapse. The result is behavioral activation
in animals, and symptoms such as euphoria, increased alertness and energy, and
sleeplessness in humans.
Autoreceptors-- found in the cell bodies, axon terminals and dendrites of dopaminergic
and noradrenergic neurons. The effect of binding of the neurotransmitter to these
autoreceptors is the inhibition of the release of the neurotransmitter into the synapse.
a. Autoreceptors in the cell bodies and dendrites reduce the rate of firing of the neuron.
b. Autoreceptors in the axon terminal reduce the rate of release of catecholamines
from the vesicles by blocking calcium channels.
How are catecholamines inactivated?
1. Reuptake-- DA and NE transporters that return these neurotransmitters to the axon
terminal, where they are either re-packaged and re-released or broken bown by
enzymes.
2. Enzymatic breakdown-- There are two enzymes that break down DA and NE into
inert components: monoamine oxidase (MAO) and catechol-O-methyltransferase
(COMT).
Some drugs that affect reuptake:
1. Tricyclic antidepressents-- block the transporters for NE and serotonin
2. Reboxetine-- just blocks the NE transporter
3. Cocaine- inhibits the reuptake of DA, NE, and serotonin (5-HT)
Some drugs that affect the enzymes:
MAO inhibitors (phenelzine, tranylcpromine)
COMT inhbitors (entacapone, tolcapone)
Block the enzymes that break down DA & NE (and 5-HT, in the case of MAO inhibtiors),
increasing the amount of these neurotransmitters in the synapse.
DOPAMINE
The vast majority of dopaminergic neurons have their cell bodies in either the substantia
nigra or the ventral tegmental area (VTA). Both areas are part of the tegmentum.
Three major dopaminergic pathways in the brain:
1. Nigrostriatal tract-- the axons from these dopaminergic neurons extend from the
substantia nigra to the striatum; this pathway is important for the regulation of
movement and it is the pathway that is damaged by Parkinson's disease.
2. Mesolimbic dopaminergic pathway-- the axons start in the VTA and extend to the
limbic system, including the nucleus accumbens, amygdala and hippocampus.
3. Mesocortical dopaminergic pathway-- the axons start in the VTA and extend to
various cortical areas, including the prefrontal cortex, cingulate gyrus, and entorhinal
cortex.
Pathways 2 and 3 are considered the major reward pathways of the brain and are
implicated in addiction.
Less prominent is the tuberhypopheseal dopamine pathway, which starts in the
hypothalamus.
What happens if you damage dopaminergic pathways?
Bilateral lesions in animals produce sensory neglect (they don't pay attention to stimuli
in their environment), motivational deficits (e.g.,they show little interest in food or water),
and motor impairments (e.g., difficulty initiating movement).
Unilateral lesions (i.e., on one side only) cause the animal to lean toward the side that
corresponds with the lesioned brain area.
Dopamine receptors-- There are different subtypes of receptors for DA, but we will focus
on two:
D1 receptors-- stimulate the enzyme adenylyl cyclase, which catalyzes the synthesis of
a second messenger called cAMP. This second messneger stimulates the production
of a protein kinase that changes the structure of various proteins in the postsynaptic
neuron.
D2 receptors-- inhibit adenylyl cyclase, thus blocking the synthesis of cAMP.
Some dopamine agonists such as apomorphine stimulate both D1 and D2 receptors,
causing behavioral activation.
Dopamine antagonists, such as haloperidol, suppress certain kinds of behavior and
cause catalepsy (lack of spontaneous movement). D2 receptor antagonists have been
used in the treatment of schizophrenia, although they can produce undesirable motor
side effects.
Let's compare the effects of two drugs: haloperidol and 6-hydroxydopamine (6-OHDA).
6-OHDA is a neurotoxin that kills dopaminergic neurons; haloperiodol is a D2 receptor
antagonist.Both cause a decrease in the binding of DA to receptors, but for different
reasons. In the case of 6-OHDA, there is less dopamine because the neurons that
produce are DEAD. In the case of haloperidol, the neurons may be alive, but the
binding of DA to the receptor is blocked. IN both cases, the postynaptic neurons will
produce an increase in the number of dopamine receptors to compensate for the lack of
DA binding. This is called up-regulation.
2/7/08CH.3 (Continued)
Figure 3.14-- Mechanisms by which drugs can alter synaptic transmission.
1. Acts as a precursor for a neurotransmitter-Example: L-DOPA is a precursor for dopamine
2. Inhibits neurotransmiiter (NT) synthesis-A form of tyrosine inhibits the enzyme (tryrosine hyroxylase) that catalyzes the reaction
which forms dopamine and norepinephrine.
3. Prevents NT storage in the vesicles-Example: Reserpine (a drug that reduces high bp) blocks the storage of dopamine,
norepinephrine, and serotonin.
4. Stimulates release of NT-Example: amphetamine stimulates exocytosis of dopamine and norepinephrine.
5. Inhibits the release of NT-Example: botox inhibits release of acetylcholine
6. Stimulates postsynaptic receptors (acting as an agonist for the NT)-An agonist either heightens the effect of the neurotransmitter or mimics that effect.
Example: Opiates stimulate opioid receptors.
7. Blocks postsynaptic receptors (acting as an antagonist)Example: Antipsychotic drugs are antagonists that block dopamine receptors.
8. Stimulates autoreceptors, which inhibits the release of the NTExample: clonidine reduces the symptoms of opiate withrrawal by stimulating the
autoreceptors that inhibit the release of norepniphrine and serotonin.
9. Blocks autoreceptors, thus stimulating release of the NTExample: Yohimbine blocks autoreceptors for norepinephrine, trigger a flood of NE into
the synapse, and thus producing the symptoms of a panic attack.
10. Inhibits NT degradationExample: MAO inhibitors block the enzyme monoamine oxidase (MAO), which breaks
down dopamine, serotonin, and norepinephrine.
11. Blocks NT reuptake
Example: Cocaine binds to dopamine transporters and thereby blocks reuptake of DA.
ENDOCRINE SYSTEM- The glands of the body and the hormones they produce
(secrete).
Both hormones and neurotransmitters interact with receptor proteins.
Drugs interact with hormone systems as well as neurotransmitter systems.
The correspondence between the glands of the endocrine system and the chakra
system:
1st Chakra-- Prostate gland in men (seminal fluid)/ Skene's glans (female ejaculation)
2nd Chakra-- Gonads
Ovaries-- estrogens (estradiol) and progesterone
Testes-- androgens (testosterone)
3rd Chakra-- Adrenals and Pancreas
Pancreas-- located between the adrenals, just above the kidneys
secretes insulin and glucagon, both of which regulate blood sugar
Adrenals have two components:
1. Inside (adrenal medulla) secretes epinephrine and norepinephrine, which mobilize
glucose and provide immediate energy for a fight-or-flight response
2. Outside (adrenal cortex) secretes glucocorticoids (e.g., cortisol), which maintain
blood glucose levels and help store excess glucose for future use.
4th Chakra-- Thymus
Secretes thymic hormones that regulate the immune system
5th Chakra-- Thyroid
Found in the throat area; secretes thyroxine and triiodothyronine, which are important
for energy metabolism
Underactive thyroid (hypothyroidism)-- weakness and fatigue
Overactive thyroid (hyperthyroidism)-- excessive energy and nervousness
6th Chakra-- Hypothalamus and Pituitary
The pituitary gland has two components:
1. anterior pituitary-- secretes hormones that stimulate the other glands of the body:
thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) stimulates the
adrenals; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the
overies; growth hormone (GH); and prolactin
2. posterior pituitary-- secretes vasopressin (antidiuretic hormone) and oxytocins
(stimulates uterine contractions in labor and lactation).
The hypothalamus releases hormones that activate the pituitary: a) thyrotropinreleasing hormone (TRH) stimulates the release of the TSH by the anterior pituitary; b)
corticotropin-releasing hormone (CRH) stimulates the release of ACTH; c)
gonadotropin-releasing hormone (GnRH) stimulates the release of LH and FSH.
7th Chakra
Pineal gland-- located over the brain stem in the center of the brain; secretes melatonin,
which is associated with the body clock and the sleep-waking cycle.
Two roles of testosterone:
1. In early development, it acts within the brain to determine gender.
2. In puberty, plays a role in stimulating sexual desire in both genders.
Two types of hormones-- Peptide hormones (amino acids) and steroid and thyroid
hormones (lipids)
Peptide hormones-- attach to extracellular (membrane) receptors and act just like
metabotropic neurotropic neurotransmitters, working through a second messenger.
Steroid and thyroid hormones-- use intracellular receptors located within the cell
nucleus, and act as transcription factors that turn on or off the expression of a specific
gene, which in turn affects protein synthesis
2/5/08CH.3
Synapse- the fundamental unit of neurotransmission that includes the presynaptic
terminal, synaptic cleft, and part of the postsynaptic cell
presynaptic terminal-- axon terminal on the neuron that is sending the message
postsynaptic neuron-- neuron receiving the message
synaptic cleft-- gap between the two neurons (20nm)
Types of synapes:
1. axodendritic synapse-- most common;; axon terminal from the presynaptic neuron
communicates with a dendrite on the postsynaptic neuron.
2. axosomatic synapse-- axon terminal communicates with a neuron cell body
3. axoaxonic-- axon terminal communicates with another axon; these types of
synapses generally modulate or regulate neurotransmitter release.
neuromuscular junction-- connection between a neuron and a muscle; although it's not
technically a synapse, it has similarities to a synapse.
Neurotransmitters-- these are the chemical messengers of the nervous system. The
definitional criteria for neurotransmitters are:
1. The presynaptic neuron manufactures and contains it.
2. The substance is released from an axon terminal.
3. It binds with receptors on the postsynaptic neuron.
4. The binding of the molecule (or of an agonist) with the receptor triggers an effect.
5. Applying an antagonist that blocks the receptor inhibits the molecule's effect.
6. There is a mechanism for inactivating this substance.
Types of neurotransmitters:
1. Amino acids (Glutamate/GABA)
2. Monoamine (Dopamine, Serotonin, Norepinephrine)
3. Acetylcholine
4. Neuropeptides (Endorphins)-- chains of amino acids
5. Lipids (Anandamide)-- long-chain hydrocarbons, includes fats
6. Gases (nitric oxide, NO)
Neuropeptides are distinct from the other neurotransmitters in that they are made in the
cell body, unlike other neurotransmitter which are made in the axon terminal. As a
result, neuropeptides are replenished more slowly than other neurotransmitters.
The steps in neurotransmission:
1. Neurotransmitter is synthesized in the presynaptic neuron and stored in vesicles
(sac-like structure that can contain and transport as many as several thousand
neurotransmitter molecules).
2. The action potential moves down the membrane of the presynaptic neuron until it
reaches the axon terminal.
3. Upon reaching the axon terminal, it opens up calcium channels.
4. Calcium ions flow into the terminal.
5. Calcium causes vesicles to fuse with the the membrane of the axon terminal
(exocytosis).
6. Neurotransmitters get released from the terminal.
7. Neurotransmitters bind to receptors on the membrane of the postsynaptic neuron.
8. The binding results in an opening or closing of ion channels in the postynaptic
neuron.
9. The net effect is either an excitatory postsynaptic potential (EPSP; depolarization) or
an inhibitory postsynaptic potential (IPSP; hyperpolarization).
10. Vesicle gets retrieved from the plasma membrane.
11. The neurotransmitter is released from the receptor and becomes inactivated.
Factors that regulate the rate at which neurotransmitters are released by the
presynaptic neuron:
1. The rate of cell firing (how many action potentials move along the membrane per unit
time).
2. Probability that the neurotransmitters will be released from the axon terminal as a
result of an action potential (sometimes an action potential does NOT result in
exocytosis, or the release of neurotransmitters).
3. The presence of autoreceptors. There are two types of autoreceptors:
a) Terminal autoreceptors are found on the axon terminal and are specific to the
neurotransmitter released by that terminal; the binding of the neurotransmitter to this
receptor inhibits the release of more neurotransmitters.
b) Somatodendritic autoreceptors. These are found on either the cell body or the
dendrites of the presynaptic neuron; binding of the neurotransmitter to these receptors
inhibits cell firing.
4. Axoaxonal synapses have heteroreceptors (receptors for a neurotransmitter that is
released by another neuron) that may either enhance or reduce the amount of
neurotransmitter released.
Inactivation of the neurotransmitter:
1. Enzymatic breakdown. An enzyme breaks down the neurotransmitter into smaller
and inert pieces.
2. Neurotransmitter is removed from the synaptic cleft by a transporter (protein) found
on the membrane of the presynaptic neuron (REUPTAKE).
3. Neurotransmitter can also be removed from the synapse by a transporter on a
neighboring cell (UPTAKE).
Cocaine binds to transporters for dopamine, serotonin and norepinephrine, preventing
those neurotransmitters from undergoing reuptake.
Two key concepts for understanding receptors:
1. Almost all neurotransmitters have more than one receptor (there are different
receptor subtypes for the same neurotransmitter).
2. Most receptors fall into two categories:
a) Ionotropic-- fast acting; the receptor has an ion channel at its center that is opened or
closed when the neurotransmitter binds to it.
b) Metabotropic- slow-acting; the receptor is composed of a single large protein that
triggers a chain reaction in the postsynaptic neuron. This chain reaction involves the
activation of G-proteins, which in turn trigger a chain of events that cause an ion
channel to open up somewhere in the cell at some point in the future.
G proteins operate by two mechanisms:
1. They can stimulate or inhibit the opening of an ion channel in the cell membrane.
2. They can stimulate certain enzymes on the membrane of the postsynaptic neuron,
called effector enzymes. Most of these enzymes are involved in the synthesis or
breakdown of a second messenger that initiates a biochemical reaction within the cell.
The second messenger activates an enzyme called a protein kinase. This enzyme
adds a phosphate group to another protein (phosphorylation); the protein on which this
enzyme acts can be an ion channel, an enzyme involved in neurotransmitter synthesis,
a receptor, a transporter, a structural protein, or a different kind of protein. The
phosphorylation reaction can change the function of a protein in some important ways
(e.g., it can ause an ion channel channel to open, can make a receptor more sensitive
to a neurotransmiiter, or can cause a protein to be produced that turns on or off a
specific gene in that neuron).
1/31/08The Nervous System
Fig. 2.15
Central nervous system-- brain and spinal cord
Peripheral nervous system-- everything else
PNS can be subdivided into:
Autonomic nervous system- innervates the internal organs
sympathetic nervous system-- energy utilization, specifically in response to
environmental stressors (i.e., the "fight-or-flight" response)
parasympathetic nervous system-- energy conservation and metabolism (e.g.,
digestion)
Somatic nervous system-- innervates the skeletal muscles
sensory afferent-- nerve that delivers signal from sense organs (e.g., receptors on the
skin) to the spinal cord
motor efferent-- nerve that delivers a signal from the spinal cord to the muscle of the
body
nucleus-- within the central nervous system, is a cluster of neuronal cell bodies
tract-- within the CNS, is a bundle of axons
ganglion-- within the peripheral nervous system, is a cluster of neuronal cell bodies
nerve-- within the PNS, is a bundle of axons
meninges-- three layers of membranes that surround the brain and spinal cord; they
also hold the cerebrospinal fluid (CSF), which helps to protect the brain and spinal cord
and also in the exchange of nutrients and waste with the blood.
ORGANIZATION OF THE ADULT HUMAN BRAIN
I. Spinal cord-- motor neurons send information to the muscles through the ventral horn
of the spinal cord, and sensory receptors send information to the brain through the
dorsal horn.
II. MyelencephalonA. medulla-- regulates vital functions, including heart rate, digestion, respiration, blood
pressure, coughing and vomiting
1. area postrema- it has less of a blood-brain barrier than other brain areas; this
allows toxins into this area that would not enter other brain areas. If there are enough
toxins and they are sufficiently noxious, they will be expelled.
III. Metencephalon
A. pons- At its core is the reticular formation, which is a se to nuclei that are important
for arousal and attention (sleep-waking cycle), muscle tone, cardiac and respiratory
reflexes.
Two sets of nuclei of the reticular formation are especially pertinent to this course:
1. locus coeruleus-- where the vast majority of neurons that produce norepinephrine are
found (these neurons are called "noradrenergic"); they stimulate arousal, vigilance and
attention. The amphetamines trigger noradrenergic pathways in the brain, enchancing
alertness and causing sleeplessness.
2. raphe nuclei (this is a set of nuclei that includ the dorsal and median raphe)-- where
most of the neurons that produce serotonin (these are called "serotonergic"); they are
important in regulating sleep, aggression, impulsiveness, and other emotions (serotonin
is often an inhibitory neurotransmitter)
B. cerebellum-- involved in muscle coordination, balance, timing of movements, and
smooth muscle movements
IV. Mesencephalon (midbrain)
A. tectum1. superior colliculus-- reflexes of the visual system (such as pupillary reflex)
2. inferior colliculus-- the auditory system
B. tegmentum
1. periaqueductal gray (PAG)-- surrounds the aqueduct that connects the third and
fourth ventricle; has large concentrations of opioid receptors, which means that it is
involved in the control of pain.
2. substantia nigra-- contains neurons that produce dopamine (dopaminergic); the
nigrostriatal tract in initiation of movement; damage to this area is associated with
Parkinson's disease
3. ventral tegmental area (VTA)-- dopaminergic neurons in this brain area have axons
that become two important tracts in the brain's reward system: mesolimbic tract
connects the VTA to the nucleus accumbens and the amygdala; the mesocortical tract
connects to the prefrontal cortex (the orbitofrontal cortex, OFC) and the cingulate gyrus.
V. Diencephalon
A. Thalamus-- relay station by which sensory impulses are distributed to the
appropriate parts of the cortex. Four out of the five senses go through the thalamus
(NOT olfaction)
B. Hypothalamus-- Regulates virtually every basic drive, including hunger, thirst, body
temperature, sexual behavior, and some emotional behavior. Controls the sympathetic
and parasympathetic nervous system through its connection to the pituitary gland.
VI. Telencephalon
A. Basal ganglia-- motor control, also play a part in the reward pathway
1. Caudate nucleus
2. Putamen
3. Globus pallidus
4. Nucleus accumbens
Caudate and putamen make up the "striatum"
B.
1.
2.
3.
4.
Limbic system
Cingulate gyrus-- involved in the emotional component of pain
Olfactory bulb
Hippocampus- memory, specially long-term memory and spatial memory
Amygdala-- processing emotion, especially fear
C. Neocortex-- Two cerebral hemispheres connected by a set of fibers called
commissures, the largest of which is the corpus collosum). Each hemisphere is in turn
divided into four lobes:
1.
2.
3.
4.
Occipital-- vision
Temporal-- hearing
Parietal-- somatosensory cortex (awareness of touch, temperature and pain)
Frontal-- motor cortex (where movement is initiated)
a. Prefrontal cortex-- decision-making, planning, evaluation of strategies, and
impulse control
1/29/08CHAPTER 2
Neurons
Three types of neurons in the NS:
1. Sensory neurons-- transducers, which convert some kind of external energy (light,
mechanical energy) into electrochemical impulses.
2. Motor neurons-- trigger a muscle contraction
3. Interneurons-- only connected to other neurons within the central nervous system
(CNS); they tend to be connected in complex networks
Structure of neurons
1. dendrites-- receive signals from either other neurons or other parts of the same
neuron; they are covered with dendritic spines, which are projections that increase the
receptive area of the dendrite
2. axons- each neuron has only one axon even though it can have many dendrites; an
axon can be branched, meaning that it has side branches called axon collaterals.
At the end of the axon is the terminal button (axon terminal) which is where
neurotransmitters are released.
Synaptic vesicles-- these carry neurotransmitters from the soma, or cell body, to the
terminal button.
Myelin-- fatty insulating coating ("Lorenzo's Oil")
nodes of Ranvier-- spaces in between the myelin coating where action potentials can
occur.
3. soma-- the cell body, which contains:
nucleus-- contains genetic material (chromosomes) and also transcription factors
(proteins that aid in the manufacture of proteins)
transcription-- the manufacture of mRNA from the DNA in the nucleus
translation-- mRNA-coded manufacture of proteins, which happens in the ribosomes
mitochondria-- glucose is converted to ATP, which is the fundamental energy storage
unit in the body
Ion channels-- found in the membranes of neurons. Their characteristics include:
1. They are relatively specific in terms of allowing certain ions through (sodium,
potassium, calcium, and chloride channels are most common in neuronal membranes).
2. Most ion channels are closed the majority of the time, and only open on a very
temporary basis. Such channels are called gated channels.
3. There are two types of gated channels:
a. Ligand-gated-- a ligand such as a drug, hormone or neurotransmitter binds to a
receptor that opens the channel.
b. Voltage-gated-- a change in voltage across the membrane caused the channel to
open.
negative voltage-- more negative than positive ions inside the membrane
positive volltage-- more positive ions inside the membrane
With voltage-gated channels, there is only a specific range of voltages in which the
channel opens.
4. The flow of ions through the channel depends on:
a. Concentration gradient-- Dissolved substances move from areas of greater
concentration to areas of lower concentration.
b. Electrical gradient (electrostatic potential)-- Ions move towards the opposite charge
and away from the same charge.
If there is a negative voltage, that is going to drive positive ions into the neuron.
Glial cells- Support cells of the nervous system, which provide insulation, protection,
and metabolic support.
Four types of glial cells:
1. Oligodendroglia- Produce myelin on axons of neurons in the CNS; each glial cell is
dedicated to myelinating a single neuron.
2. Schwann cells-- Produce myelin on axons of neurons in the PNS; one glial cell can
serve several neurons.
3. Astrocytes-- structural support to neurons and regulate the chemical environment,
helping to move nutrients from the blood into the neuron and waste from the neuron into
the blood.
4. microglia-- scavengers, remove dying cells; help in the immune response of the CNS
Electrical potentials in the nervous system:
Resting potential-- at rest, the voltage of most neurons is -70 mV (the inside of the
membrane is more negative than the outside)
Forces responsible for the resting potential:
1. Concentration gradient
a. drives sodium ions into the neuron
b. drives potassium ions out
2. Electrical gradient
a. drives sodium ions in
b. drives potassium ions in
3. Potassium channels are not gated, which means that potassium ions can move
relatively freely.
Equilibrium potential is reached in which the numbers of potassium ions going in is
equal to that going out.
4. Sodium-potassium pump
At times, sodium leaks into the cell at rest, and the sodium-potassium pump moves
sodium out while bringing potassium in. For every 3 sodium ions that are pumped out,
2 potassium ions are pumped in.
depolarization-- When a membrane at rest becomes more positive (or less negative),
moving closer to 0mV
hyperpolarization-- When a membranes becomes more negative
Local potentials-- These happen on dendrites and cell bodies. They have the following
characteristics:
1. are graded-- the larger the electrical stimulus, the greater the potential
2. decay rapidly
3. summation-- several depolarizations and/or hyperpolarizations can be added
together
Action potentials-- these are potentials that are transmitted through the axon
membrane, and they get regenerated at different points along the membrane
Here is how they work:
1. The potential increase from a resting potential of -70mV to -50mV, which is the
threshold potential.
2. Sodium channels open and sodium ions pour into the axon.
3. The voltage changes immediately from -50mV to +40mV
4. When the voltage hits +40mV, the sodium channel closes again
(These channels are gated in such a way that they only open between -50 and +40mV)
5. Sodium-potassium pum-- moves two potassium ions in for every three sodium ions
that it removes.
Why does the resting potential start at -50mV instead of just zero?
Having a negative potential at the start of the action potential speeds up that potential,
increasing the rate with which the sodium ions flow across the membrane.
Action potentials follow the all-or-none law. If the membrane is depolarized enough to
hit its threhold potential, the action potential is going to happen. A greater
depolarization doesn't result in a greater potential.
In myelinated axons, the speed of conduction is 15 times faster than in unmyelinated
axons. The process of transmission of the potential along the membrane of a
myelinated axon is called saltatory ("jumping") conduction.
Local anesthetics- Block sodium channels so that pain signals can't reach the CNS
procaine (Novocaine), lidocaine (Xylocaine), benzocaine (Anesthesin)
1/24/08Announcements:
Syllabus, study guide, and lecture notes are posted at: http://vas.web.arizona.edu
EliminationFirst-order kinetics-- The rate of elimination of a drug from the body is an exponential
function of the concentration of the drug in the blood stream, so that 50% of the free
remaining drug is removed at each interval.
Zero-order kinetics-- Drug is eliminated at a constant rate, purely as a function of time,
and regardless of its concentration in the bloodstream. Example: alcohol.
The single most important route of elimination of drugs from the body is through urine.
The liver produces enzymes that help break down the drug and ionize it into a form that
can be dissolved easily and passed through urine.
Pharmacodynamics
The mechanism of action of drugs in the body, which involves binding to receptors.
With psychoactive drugs, the receptors are associated with neurons somewhere in the
nervous system.
Receptors are proteins that are either found on the surface of cell membranes
(extracellular) or inside the cell (intracellular).
Substances that bind to receptors are ligands, and the most common ligands are
neurotransmitters, hormones, and drugs.
The biggest difference between a neurotransmitter and a hormone has to do with how
distributed its effects are on the body. Neurotransmitters tend to be localized whereas
hormones are distributed widely throughout the body.
Agonist vs antagonist-- An agonist is a ligand that binds to a receptor and activates it.
An antagonist blocks the activity of the receptor, either directly or indirectly.
Competitive vs. non-competitive antagonists-- A competitive antagonist competes with
the agonist for binding sites on the receptor. Example: naloxone competes with
morphine and blocks it effects on the body.
A non-competitive antagonist reduces the effect of the agonist without necessarily
competing with it for binding sites on the receptor. Example: chlorothiazide (CTZ), a
diuretic that indirectly interferes with glutamate receptors.
Characteristics of receptors:
1. They have the ability to recognize specific molecular shapes (lock-and-key model).
2. The binding of the ligand is temporary.
3. The shape of the receptor changes as a result of binding by the ligand; this change
triggers a chain of intracellular events that produce a specific effect (e.g, opening up ion
channels in a neuron).
4. Receptors are proteins that have a specific life cycle; they can be modified in terms
of number and sensitivity.
Up-regulation (increase in the number of receptors) and down-regulation (decrease in
the number of receptors).
The potency of a drug is a measure of the amount of the drug needed to produce a
desired effect. Potency is a function of:
Affinity- Attraction of the drug to the receptor (how well does it bind)
Efficacy- Ability of the drug to trigger a certain action by the recepto once it does bind.
ED50-- The dose that produces 50% of maximal effectiveness. Ideally, drug
manufacturers want this number to be as low as possible, meaning that the drug
produces a relatively large effect with a relatively small dose.
TD50-- The dose that produces 50% of maximal toxicity. Ideally, drug manufacturers
want this number to be as high as possible, meaning the it takes a large dose to
produce toxicity.
Therapeutic index-- The ratio of TD50/ED50. The larger the effective dose is, compared
to the toxic dose, the better.
Tolerance-- Diminished response to a drug after repeated exposure to it.
Characteristics of tolerance:
1. It's reversible. If you stop taking a specific drug, the tolerance gets reduced.
2. It depends on the pattern of drug use. Higher frequency and dosage produces more
tolerance.
3. It depends on the type of drug. Some drugs produce rapid tolerance (LSD), some
produce slow tolerance, and some no tolerance (antipsychotics).
4. It depends on the effect-- With morphine, the nausea produced by the drug has rapid
tolerance, whereas the constipating effect has no tolerance.
5. It can have different mechanisms, such as:
metabolic tolerance (drug disposition)- This occurs when repeated use of the drug
reduces the amount available at binding sites, probably because of enzyme induction.
More drug in the system equals more enzymatic breakdown of that drug.
pharmacodynamic tolerance-- This is a change in nerve cell function that compensates
for continued presence of the drug (down-regulation).
Homeostatic processes that compensate for an imbalance resulting from drug use.
behavioral tolerance-- This occurs when drug effects diminish only in certain
environments that are associated with drug administration but not in novel
environments.
habituation- Desensitization to familiar vs novel stimuli. Orienting response-- You hear
a buzzer goes off and your brain produces an evoked potential. The amplitude of that
potential decrease with repeated exposure to the same stimulus.
classical conditioning-- can explain some types of tolerance. Tolerance may start out as
an unconditioned response to the stimulus (i.e., the drug) but then it can become a
conditioned response to environmental cues.
operant conditioning-- If you're rewarded for showing less of an effect of a drug, then
you will start to show less of an effect (Example: If you're rewarded for driving
effectively under the influence of the drug, then you will learn to function better as a
driver under the influence).
state-dependent learning-- Tasks learned under the influence of a psychoactive drug
are performed better under the influence of that drug. The drug effect becomes part of
the environmental cues for memory retrieval.
1/22/08Study guide is at http://vas.web.arizona.edu, along with the syllabus. Lecture notes will
be posted there, as well.
CH.1- Principles of Pharmacology
What is pharmacology? It's the study of the action of drugs and their effects on living
organisms.
Pharmacology can be divided into three sub-disciplines:
1. Neuropharmacology-- focuses on the effects of drugs on the nervous system.
2. Psychopharmacology- focuses on the effects of drugs on the mind (experience,
thought, and action).
3. Neuropsychopharmacology- focuses on the development of drugs that counter the
effects of injury, disease or other damaging environmental factors.
Drug effects can be categorized as follows:
therapeutic vs side effects-- therapeutic effects are intentional physical or psychological
effects, whereas side effects are unintentional.
specific vs non-specific effects-- specific effects are based on drug-receptor interactions
that can be predicted; non-specific effects are due to personality factors (P), situational
or environmental factors (E) and the interaction of the two (P x E), which are much less
predictable. Included among non-specific effects are placebo effects, which are the
effects produced as a result of taking an inert substance.
Pharmacokinetics-- The study of the factors that affect the rate with which drug effects
are initiated and terminated.
These factors include:
1. Route of administration-- How and where a drug is delivered into the body.
2. Absorption and distribution-- How the drug enters the bloodstream and where it is
delivered by the blood.
3. Binding-- How the drug binds to receptors.
4. Inactivation-- Breakdown of the drug through some metabolic process into an inert
form.
5. Excretion-- How the drug is eliminated from the body.
I. Routes of Administration
a) Oral--- Taken through the mouth, usually in the form of a pill or capsule.
b) Intravenous-- Injected directly into the bloodstream, through a vein.
c) Intramuscular-- Injected into muscle tissue.
d) Subcutaneous-- Injected just below the skin
e) Inhalation-- Absorbed through the longs (smoking)
f) Topical-- Application to the mucous membranes (e.g., snorting)
g) Transdermal-- Through the skin (nicotine patch, scopolamine)
h) Epidural-- Injection into the cerebrospinal fluid (CSF), used with drugs that would not
cross the blood-brain barrier fast enough otherwise.
IV use poses several hazards:
1. Drugs that are impure or of unknown quality can produce overdose or poisoning.
2. Lack of sterile needles and procedures can lead to infections such as hepatitis and
HIV>
3. Filler materials in IV drugs that don't dissolve properly and create clots and other
blockages in the body.
II. Absorption
Absorption of the drug is determined by several factors:
1. Route of administration-- affects where the drug is absorbed and the amount of the
drug destroyed by metabolic processes.
2. Drug concentration-- Depends on dosage, but also on age, sex, and body size.
3. Differences in solubility and ionization of different drugs
The ionization of a drug, which is usually a salt of some kind, is the breakdown of the
drug molecules into positive and negative ions. The rate of ionization of a drug depends
on:
a. pH (measure of the acidity/alkalinity of a solution)-- Drugs that are weak acids
dissolve and ionize better in alkaline solutions, and weak bases ionize better in acidic
solutions.
b. pKa-- The equilibrium constant for the dissociation or ionization of a drug; this is an
inherent or intrinsic characteristic of the drug.
The ionized form of a drug does not get absorbed by membranes as effectively as the
non-ionized form.
The membranes found in the lining of the stomach and intestines are made up of
phospholipids. The phosphate "head" of these molecules is hydrophilic ("water loving")
and therefore dissolve in water. The hydrocarbon "tail" is hydrophobic ("water fearing")
and therefore not only do not dissolve in water but also repel substances that are ionic
or polar.
Why do so many prescribed drugs have to be taken just before a meal and with water?
The stomach empties into the small intestine faster when it's empty, and the small
intestine has more surface area and slower movement of material than the stomach,
allowing greater absorption of the drug.
III. Distribution
Highest concentrations of a drug that has been ingested are in organs that have a high
blood flow, such as the heart, brain, kidneys, and liver.
In theory, the brain, which has a very high blood flow, should be inundated with drugs,
but it's not because of the blood-brain barrier.
This barrier consists of endothelial cells that make up the walls of brain capillaries. The
cells have tight junctions that restrict the movement of substances out of the capillary
and into the brain.
The same kind of barrier can be found in the placenta. Some drugs pass through this
placental barrier relatively easily, including opiates, alcohol, barbiturates, cocaine, and
carbon monoxide from smoking. Many of these substances are teratogens (cause birth
defects in a developing fetus).
IV. BINDING
Binding to receptors in the brain is the topic of pharmacodynamics (next section).
Depot binding is the binding of drugs to inactive sites in the body, such as blood
plasma, muscles, fat, and bone, where drugs accumulate. The effects of depot binding
include:
1. Lowered concentrations of the drug at sites of action because only freely-circulating
drugs can bind to these sites. This can slow the onset of a drug or reduces its effects.
2. Competition among different drugs for depot-binding sites can produce higher
concentrations than expected of a drug (in the bloodstream); this is the source of certain
drug interactions.
3. Bound drugs cannot be metabolized by liver enzymes because they don't make it
into the liver (some drugs, such as THC, can stay in your system for weeks after you've
taken it).
4. Binding to depots may inactivate the drug, at least temporarily.
V. INACTIVATION
Biotransformation (metabolism of a drug into an inactive form) is of two types:
Type I-- The breakdown of the drug into smaller components through oxidation,
reduction, and hydrolysis.
Type II-- The drug can combine with other molecules to form new, larger, and also
inactive substances.
Factors that affect drug metabolism or inactivation:
1. enzyme induction-- many drugs cause an increase in the levels of the liver enzymes
that biotransform them.
2. enzyme inhibition-- other drugs can inhibit the action of enzymes (MAO inhibitors).
3. drug competion-- a drug may block the breakdown of another drug
4. individual differences that cause some people to metabolize a drug more efficiently
than others (factors such as genetics, age, and gender can affect metabolic rates).