Depressants and stimulants

advertisement
CHAPTER 5
Drugs, Addiction,
and Reward
Psychoactive Drugs
Psychoactive Drugs
• Drug : a substance that on entering the body changes
the body or its functioning.
– An agonist mimics or enhances the effect of a
neurotransmitter.
– An antagonist may occupy the receptors without activating
them, simultaneously blocking the transmitter from binding
to the receptors.
• Psychoactive drugs are those that have psychological
effects, such as anxiety relief or hallucinations.
Psychoactive Drugs
• Addiction:
–
–
–
–
Preoccupation with obtaining a drug
Compulsive use of the drug in spite of adverse consequences
High tendency to relapse after quitting
Typically defined as an individual showing both withdrawal and tolerance.
• Withdrawal:
– Negative reaction that occurs when drug use is stopped
• Negative = opposite of drug effect
• Negative also means “bad” to many people
– Body’s compensatory reaction.
• Tolerance:
– Individual becomes less responsive to the drug
– Requires increasing amounts of the drug to produce the same results.
Psychoactive Drugs:
opiates
• Opiates
– Natural forms derived form the opium poppy.
– Can also be synthetically made
– Act on opiate receptors or endorphin receptors
• Several important effects:
– Analgesic (pain relieving)
– Hypnotic (sleep inducing)
– Produce a strong euphoria (sense of happiness of ecstasy).
Psychoactive Drugs:
opiates
•
Types of opiates:
– Morphine: pain relief, surgical pain relief, cancer
• Derivatives include codeine, vicodin, oxycotin, etc...
• Synthetic or natural
– Heroin
• Synthesized from morphine; originally by C. R. Alder Wright in 1874
• Marketed as an over-the-counter analgesic until its dangers were recognized
• Now a Schedule 1 (illegal) drug.
• In 2004, Afghanistan produced roughly 87% of the world supply in illicit raw
opium.[; Mexico has increased production sixfold from 2007 to 2011, making
Mexico the second largest opium producer in the world
• 2-4 times more potent than morphine and is faster in its onset of action.
– Illicit heroin also made into white powder freebase form.
– Because of its lower boiling point, the freebase form of heroin is smokable.
Opiate drug action
• Endorphins: Endogenous opiates
– body produces its own natural opiates,
which are neuromodulators
– Released when in pain, motor exertion,
stress
– Endogenous = made by the body.
• Opiate drugs are effective because
they mimic endorphins
• Because of CNS effects and cognitive
effects, very high likelihood of abuse.
Psychoactive drugs:
the depressants
• Depressants: Drugs that reduce central nervous system
activity.
• Sedatives: calming drugs (hypnotic or sleep inducing as well)
• Most common:
–
–
–
–
–
–
Barbiturates
Anxiolytics
Hypnotics
Antihistamines
Other nonhynpotic depressants
Alcohol
Psychoactive drugs:
the depressants
• Anxiolytic: Anxiety-reducing drugs:
– Most common category are the Benzodiazepines ("minor
tranquilizers")
•
•
•
•
•
•
•
•
•
•
•
Klonopin;
diazepam (Valium);
estazolam (Prosom);
flunitrazepam (Rohypnol) ;
lorazepam (Ativan) ;
midazolam (Versed);
nitrazepam (Mogadon) ;
oxazepam (Serax) ;
triazolam (Halcion); ;
temazepam (Restoril; , Normison, Planum; Tenox, Temaze) ;
chlordiazepoxide (Librium)
Psychoactive drugs:
the depressants
• Hypnotic drugs: induce sleep-like states: Nonbenzodiazepines:
–
–
–
–
Zolpidem;
Zaleplon;
Zopiclone;
Eszopiclone
• Antihistamines:
– Diphenhydramine (Benadryl);
– Doxylamine; Hydroxyzine; Promethazine
• Other related hypnotic drugs:
– gamma-hydroxybutyric acid (Xyrem) ; Glutethimide
– Chloral hydrate
– Ethchlorvynol Levomepromazine; Chlormethiazole
Sedative effects on the cns
• Barbiturates
– Suppress inhibitory centers of the brain
• First act on cerebral cortex
• Then to basal ganglia areas
• Finally to brain stem
– In small amounts: act selectively on higher cortical centers,
especially those involved in inhibiting behavior
– In low doses :produce talkativeness, increased social interaction,
– Higher doses: sedatives and hypnotics.
• Barbiturates and benzodiazapines do not reduce pain, but
they do reduce the anxiety associated with pain.
Sedative effects on the cns
• Barbiturates include
–
–
–
–
Amobarbital (Amytal);
Pentobarbital (Nembutal);
Secobarbital (Seconal) and
Phenobarbitol (Luminal)
• Because of hypnotic effects, disrupt sleep cycles
– Rob you of REM or dream sleep
– Long term use may affect cognition as well as upset basic
physiology
– High risk of addiction
Benzodiazepines- an
alternative to barbiturates?
• Both barbiturates and benzodiazepines produce their effects
by decreasing glutamate activity and increasing GABA
activity.
– Glutamate antagonist
– GABA agonist
• They operate at the barbiturate receptor on the GABAA
complex.
• Result is increase in GABA activity and reduction in
glutamate
– Less anxiety
– Also less memory formation
Benzodiazepines- an
alternative to barbiturates?
• A few decades ago:
– Barbiturates = drug of choice for treating anxiety
– Also as most common drug for situations requiring sedation.
• BUT: high liability potential for addiction and high rate of
accidental or intentional death.
Benzodiazepines- an
alternative to barbiturates?
• Benzodiazepines: largely replaced barbiturates
– Produce anxiety reduction
– Also induce sedation and muscle relaxation.
– operate at the benzodiazepine receptor on the GABAA
complex.
• At first, thought non-addictive
– Today know that are highly addictive
– Are less likely to cause death with overdose unless mixed
with another sedative such as alcohol or sleeping pills.
Psychoactive drugs:
Alcohol
• Ethanol, or alcohol:
– is a drug fermented from fruits, grains, and other plant products.
– Is a DEPRESSANT
• It acts at many brain sites to produce
–
–
–
–
–
euphoria,
anxiety reduction,
sedation,
poor motor coordination,
cognitive impairment
• Why is it a depressant?
– Depresses CNS
– Inhibits areas of the brain that inhibit acting out, inappropriate behavior, etc..
How does alcohol affect
the CNS?
• Alcohol inhibits the release of glutamate (the most
prevalent excitatory neurotransmitter).
– Glutamate ANTAGONIST
– Glutamate reduction produces a sedating effect
• Chronic use results in a compensatory increase in the
number of glutamate receptors,
• This increase probably accounts for the seizures that
sometimes occur during withdrawal.
How does alcohol affect
the CNS?
• Alcohol also increases the release of gamma-aminobutyric
acid (GABA)
– GABA agonist
– the most prevalent inhibitory neurotransmitter).
– Alcohol specifically affects the A subtype of GABA receptor.
• The combined effect GABA and Glutamate receptors is:
–
–
–
–
sedation
anxiety reduction,
muscle relaxation,
inhibition of cognitive and motor skills.
Alcohol abuse effects
• Cirrhosis of the liver,
– Common side effect of chronic alcoholism
– in its severest form is fatal.
–
• Vitamin B1 deficiency
– associated with chronic alcoholism
– can produce brain damage and Korsakoff’s syndrome
• Delirium tremors
– more severe reactions
– hallucinations, delusions, confusion, and in extreme cases, seizures
– possible death.
• Alcohol withdrawal symptoms
– involves tremors, anxiety, and mood and sleep disturbances;
Alcohol abuse effects
• Korsakoff’s syndrome
–
–
–
–
Neurological syndrome due to alcohol damage, B1 deficiency
involves severe memory loss along with sensory and motor impairment.
eye movement disorders
ataxia (poor motor coordination)
– Individuals show severe anterograde amnesia
• Unable to make new memories
• Unable to learn new things
– Often accompanied by seizures, depression and other psychiatric issues
• https://www.youtube.com/watch?v=AZ1Rc22MKu4
Psychoactive Agents
Stimulants
Psychodelics
Psychoactive Drugs
• Addiction:
– preoccupation with obtaining a drug
– compulsive use of the drug in spite of adverse consequences
– high tendency to relapse after quitting
– Typically defined as an individual showing both withdrawal and
tolerance.
• Withdrawal:
– negative reaction that occurs when drug use is stopped
– Body’s compensatory reaction.
• Tolerance:
– individual becomes less responsive to the drug
– requires increasing amounts of the drug to produce the same
results.
Psychoactive stimulants
• Stimulants:
– activate the central nervous system to produce
• arousal,
• increased alertness,
• elevated mood
• Typically affect dopamine, norepinephrine and
serotonin
• Several drugs in this category
– Cocaine
– Amphetamine
– Methamphetamine
– Ritalin, Adderal, and most ADHD medications
– Ephedrine
Psychoactive stimulants
• Cocaine,
– extracted from the South American coca plant,
– produces
•
•
•
•
Euphoria
decreases appetite,
increases alertness
relieves fatigue.
• Cocaine blocks the reuptake of dopamine and serotonin at synapses,
– Potentiating effect of these neurotransmitters
– Makes neurotransmitter remain longer in synapse.
• Presumably, cocaine produces euphoria and excitement because
dopamine removes the inhibition the cortex usually exerts on lower
structures.
Cocaine
user
Normal
Psychoactive Drugs
• Amphetamines
– group of synthetic drugs
– Again produce euphoria
– increase confidence
– In low doses: increases concentration.
• increase the release of norepinephrine and
dopamine: DA Agonists
Psychoactive Drugs
• Common examples:
– Amphetamine (Adderal®); Dextroamphetamine
(Dexedrine®, Dextrostat®)
– Methamphetamine (Desoxyn®)
• Highly related:Ritalin:
– Ritalina, Rilatine, Attenta, Methylin, Penid,
Rubifen); and the sustained release tablets
Concerta, Metadate CD, Methylin ER, Ritalin
LA, and Ritalin-SR. Focalin
Amphetamine Action
• DA neurons release DA into the synapse:
From there 1 of 3 things can happen:
1. DA can then attach to the post-synaptic
membrane
2. DA can be degraded by enzymes
3. DA can be taken back up by the pre-synaptic
membrane.
Amphetamine Action
• Amphetamine appears to affect all three
mechanisms:
1. Promotes release of DA into the synapse
2. Inhibits the DA degredative enzyme, monoamine
oxidase (MAO),
3. Blocks the uptake proteins in the pre-synaptic
membrane
• The result : Amphetamine effectively promotes a
flood of DA into the brain reward center:
– Nucleus Accumbens or Nac
– This area is highly involved in both learning and reward.
Amphetamine Action
• Amphetamine and related compounds elicit a
variety of dose-dependent deleterious effects.
• Low doses of AMPH may
– improve attention
– improve vigilance
• At high doses:
– over-stimulation of the motor and cognitive systems
– behavioral stereotypy, repetitive thoughts and even
hallucinations.
Amphetamine Action
• In rodents, a high AMPH dose elicits behavioral
stereotypy:
–
–
–
–
–
continuous digging
Searching
Licking
Gnawing
Circling
• In humans, high doses of AMPH may elicit:
– psychotic state,
– High rates of locomotion and repetitive behavior
– high potential for self-injury or injury to others
A normally moving rat
A rat given 8.0 mg/kg amphetamine
Psychoactive Drugs: Nicotine
• Nicotine:
– primary psychoactive and addictive agent in tobacco
– Also in chewing tobacco, nicotine gum, etc.
• It stimulates nicotinic acetylcholine receptors. ACh agonist
– In the periphery,
• it activates muscles
• may cause twitching.
– In CNS:
• produces increased alertness
• Also faster response to stimulation.
• Given peripheral effects, why might individuals on
antipsychotics or those with Parkinson’s like to smoke?
Psychoactive Drugs: Caffeine
• Active ingredient in coffee, many soda pops; teas;
energy drinks, etc.
• Produces arousal, increased alertness, and
decreased sleepiness.
• Cardiovascular response: direct stimulation of the
heart
– mitigated to some extent by concurrent vagal
stimulation.
– CNS + PNS effects sometimes result in ventricular
irritability
Psychoactive Drugs: Caffeine
• Also get direct vasodilation with concurrent
vasoconstriction from stimulation of the medulla
– Result: either increases or decreases in blood pressure.
– Smooth muscle is relaxed by caffeine, while skeletal
muscle is stimulated.
• Action: blocks receptors for the neuromodulator
adenosine: Adenosine antagonist
– Because adenosine has sedative and depressive effects, blocking its
receptors contributes to arousal
– This increases the release of dopamine and acetylcholine.
– Acts like a back door amphetamine in releasing DA.
Psychodelic Drugs
• Psychedelic drugs:
– compounds that cause perceptual distortions in the user.
– May be referred to as hallucinogenic
• Not really inducing hallucinations, but distortions in perception:
– Light and color details are intensified,
– objects may change shape,
– sounds may evoke visual experiences,
– light may produce auditory sensations.
• Synesthesia: stimulation of one sensory or cognitive pathway
leading to automatic, involuntary experiences in a second sensory or
cognitive pathway
Psychoactive Drugs
• Lysergic acid diethylamide (LSD)
–
–
–
–
best-known psychedelic
is structurally similar to serotonin
stimulates serotonin receptors
Appears to disrupt the brain stem’s ability to screen out irrelevant
stimuli.
• Psilocybin and psilocin
– Another serotonin-like psychedelics
– both derived from the mushroom, Psilocybe mexicana
• Mescaline
– the active ingredient in peyote (the crown or button on the top of the
peyote cactus),
– psychedelic properties result from stimulation of serotonin receptors.
Ecstasy or Molly
• Ecstasy or Molly: street name for a drug developed as a weigh-
loss compound methlenedioxymethamphetamine (MDMA).
• At low doses:
– psychomotor stimulant
– Increases energy, sociability, and sexual arousal.
• At higher doses:
– produces hallucinatory effects like LSD.
– Also can overstimulate muscles resulting in “locked” or frozen
muscles
– May permanently bind to MDMA receptors
• Affects learning and memory
• Affects emotions
• Affects motor movement
Ecstasy or Molly
• MDMA stimulates
– the release of dopamine which accounts for muscle
and arousal effects
– the release of serotonin, which probably accounts
for the hallucinatory effects.
• Damage to neurons much more immediate
and severe than with typical amphetamines
– Destroys autoreceptors on DA, 5HT neuron
– Overstimulates post-synaptic receptors
– Much greater and faster cell death
These brain sections
have been stained
with a chemical
that makes neurons
containing
serotonin turn
white. Photos in
the top row are
from a normal
monkey; those
below are from a
monkey given
MDMA a year
earlier.
Psychoactive Drugs:
Phencyclidine or PCP
• Developed as an anesthetic typically used by
veterinarians
• was abandoned for human use because it produces
schizophrenia-like disorientation and
hallucinations.
• PCP increases activity in the dopamine pathways
– This stimulates motivation system
– Also, drug’s motivating properties apparently are partly
due to its inhibition of a subtype of glutamate
receptors.
Marijuana
• is the dried and crushed leaves and flowers of the Indian hemp plant,
Cannabis sativa.
• The major psychoactive ingredient is delta-9-tetrahydrocannabinol (THC)
– Acts on the anterior cingulate cortex and frontal cortex
•
Other important active ingredient is Cannabidiol (CBD)
– at least 60 active cannabinoids identified in cannabis
– a major constituent of the plant, accounting for up to 40% of the
plant's extract
– is a non-psychotropic phytocannabinoid.
– considered to have a wider scope of medical applications than THC
.
Marijuana
• THC actions:
– THC binds with cannabinoid receptors, which ordinarily
respond to endogenous cannabinoids.
– Particularly in frontal lobe and cingulate cortex
– Two known cannabinoids receptors:
• anadamide
• 2-arachidonyl glycerol, or 2-AG.
• These receptors are found on axon terminals;
Marijuana
• Cannabinoids (CBD))
– released by postsynaptic neurons
– act as retrograde messengers, regulating the
presynaptic neuron’s release of neurotransmitter.
– CBD is also a 5-HT1A receptor agonist,
– CBD's antagonistic effects at the cannabinoid receptors,
compared to THC's partial agonist effect.
Marijuana: multiple forms
• Cannabis sativa: typically more likely to be used
“recreationally”
• Lower CBD: THC ratio (much more THC)
• Well known for producing a “cerebral high”- likely due
to partial AGONIST effect on cannabinoid receptors
• When used for medical purposes: often used during
daytime treatments as does not produce drowsiness
Marijuana: multiple forms
• CBD:THC ratio: ratio of cannabinoid (CBD) to THC
• Cannabis indica: “Medical marijuana”
• 4–5 times the amount of CBD to THC as found in Cannabis
sativa.
• Cannabis strains with relatively high CBD:THC ratios are less
likely to induce anxiety
• known for its sedative effects:
• more calming, soothing, and numbing experience
• can be used to relax or relieve pain.
• Also seems to reduce the frequency of seizures: probably due to
antagonist effects at cannabinoid receptor
• Also appears to serve as partial agonist for serotonin receptors
Addiction
• Reward refers to the positive effect an object or condition
– such as a drug, food, sexual contact, and warmth – has
on the user.
• Drug researchers have traditionally identified the
mesolimbicortical dopamine system as the location of the
major drug reward system.
– It takes its name from the fact that it begins in the midbrain
(mesencephalon) and projects to the limbic system and prefrontal
cortex.
– The most important structures in the system are the nucleus
accumbens, the medial forebrain bundle, and the ventral
tegmental area.
Virtually all the abused drugs increase dopamine levels in the nucleus accumbens
Why are Psychoactive Drugs “bad”?
• Do tell us a great deal about brain functioning!
• BUT: pattern of effect they produce is usually unlike normal
functioning.
• Drugs are wide acting:
– affect wide areas of the brain indiscriminately
– normal activation tends to be more discrete and localized
• Can’t control drug effects
– Not act only in ways you want them to.
– May over-stimulate, “burn out” neurons
– May result in long term damage to system
Addiction TREATMENT
• Agonist treatments replace an addicting drug with another drug that
has a similar effect.
– Opiate addiction is often treated with a synthetic opiate called
methadone.
• Antagonist treatments involve drugs that block the effects of the
addicting drugs.
– Drugs that block opiate receptors are used to treat opiate addictions and
alcoholism because they reduce the pleasurable effects of the drug.
• Another experimental strategy is to interfere with the dopamine
reward system.
– Baclofen reduces dopamine activity in the ventral tegmental area by
activating GABAB receptors on dopaminergic neurons.
Download