2009 - Lecture 8
Artificial & Natural Ligands:
Drugs
Chinese
Tea
Stimulant
Vikings
Amanita Muscaria
GABA agonist
Drugs have been used for centuries
American
Indian
Peyote
5HT & DA
agonist
Egyptians
Beer
DA & GABA
Agonist
5HT & Glutamate
Antagonist
Not just humans…
Animals self administer ETOH
coca leaf
Everybody takes drugs!..in one form or another
DRUG USE = Ubiquitous
7 out of the 10 of leading causes of disabilities
in US
Drug Use
Major depression
Manic Depressive Illness
Schizophrenia
Dementia
Degenerative CNS
OCD
Drug Abuse
2/3 of Americans older than 12 drink alcohol
 1/4 of Adult Americans are smokers
(~458 pks/year)
100gm of Caffeine/year
 1/2 of Americans older than 12 have used
illicit drugs at least once
Marijuana
Socially acceptable
National Surveys
Reported drug and alcohol use by high school seniors, 2004
Used within the last:
Drugs
12 months*
30 days
Alcohol
70.6 %
48.0 %
Marijuana
34.3
19.9
Stimulants
10.0
4.6
Other opiates
9.5
4.3
Tranquilizers
7.3
3.1
Sedatives
6.5
2.9
Hallucinogens
6.2
1.9
Cocaine
5.3
2.3
Inhalants
4.2
1.5
Steroids
2.5
1.6
Heroin
0.9
0.5
*Including the last month.
Source: Press release: Overall teen drug use continues gradual decline; but use of inhalants
rises, University of Michigan News and Information Services, December 21, 2004.
College Students
YEAR
Marijuana
Cocaine
93
94
27.9
29.3
2.7
2.0
95
96
31.2 33.1
3.6
2.9
97
31.6
3.4
98
99
00
01
35.9 35.9 35.2 34.0
4.6
4.6
4.8
4.7
Source: University of Michigan,
Monitoring the Future National Survey Results on Drug Use, 1975-2003,
Volume II: College Students, 2004.
02
03
35.6
33.7 %
4.8
5.4 %
Percent of College Students/Young Adults Using Marijuana,
2003–2004
College
Students
2003
2004
Young Adults
2003
2004
19.3%
18.9%
17.3%
16.5%
Past
year
33.7
33.3
29.0
29.2
Lifetime
50.7
49.1
57.2
57.4
Past
month
National Institute on Drug Abuse and University of Michigan, Monitoring the Future National
Survey Results on Drug Use, 1975–2004, Volume II: College Students & Adults Ages 19–45, 2005
New phenomena:
Baby boomer overdosing
197022 yrs
198532 yrs
Now 43 yrs
Cocaine
Heroin
Marijuana
1999
168,751
82,192
87,068
2000
174,881
94,804
96,426
2001
193,034
93,064
110,512
2002
199,198
93,519
119,472
Total number of drug mentions in drug abuse-related emergency department visits, by type of drug, 1999-2002
What is a drug?
Chemical that alters one or more normal
biological processes
Psychoactive, Psychotropic
Alter behavior, cognitive function or emotions
DRUGS…
Good/Bad????
 How much?
 For what reason?
 In what context?
EX: Heroin
SET: Psychological Makeup of person &
expectations
SETTING: Social  physical environment
+
biochemical  unique body chemistry
Tolerance:
state of decreased sensitivity to a drug as a result of
continued exposure to it
effect
Takes more drug to get the same affect
Dose response curve: shift to the right
dose
Tolerance???
compensatory mechanisms that oppose the
effects of the drug
Biological Tolerance: Two Types
metabolic tolerance : the body increases its ability to get rid of
the drug e.g. an increase in the level of enzymes in the body that
break down the drug
physiological tolerance: may involve compensatory changes at
a synaptic level
VERY IMPORTANT!!!
Setting: Social, physical environmental
Seigel et al. (1982)
Tested the hypothesis that setting is important in drug tolerance
Heroin can be conditioned to the environment
30 days of heroin in varying environments
Group 1
Group 2
Heroin (colony)
Placebo (noisy room)
Placebo (colony)
Heroin (noisy room)
Group 3
Placebo (colony)
Placebo (noisy room)
All animal injected with lethal dose (15mg/kg)
Colony
noisy room
colony
64% died
Only 32% died
noisy room
colony
noisy room
96% died
Lethal effects when drug was taken in new environment (no compensatory)
Conditioned Drug Response: tolerance effects (compensatory: work against
drug) are maximally shown when drug taken in same situation/ environment
Classical Conditioning Model: Heroin Overdosing
Tolerance???
compensatory mechanisms that oppose the
effects of the drug
Withdrawal symptoms are compensatory
reactions in the body that oppose the
Effects of
heroin
Heroin withdrawal
symptoms
euphoria
dysphoria
constipation
diarrhea & cramps
relaxation
agitation
Psychopharmacology:
Study of drugs on NS  behavior
What Determines Drug Efficacy?
PHARMACOKINETICS
 Absorbed
 Distributed
 Metabolized
 Eliminated
bloodstream
bloodstream
broken down
Urine, sweat
feces, mother’s milk
Pharmacokinetics
 Absorbed
 Distributed
 Metabolized
 Eliminated
Site of Action
routes of administration
IV
IP
IM
PO
Sublingual
inhalation
PO: Most common, easiest, safe, cheapest
 Swallowed
 Stomach (enzymes)
 Intestine
 Liver
bloodstream
(alcohol)
Bloodstream
Unpredictable & time consuming
PO (Cons)
 absorbed more slowly..not good for emergencies
 need to be awake..choke
 need bigger doses
 irritate stomach …eat food
Inhalation:
quick, lungs
 Lung damage
 Not precise
IM: Muscle
 more rapid/PO
 hurts!!
IV: Strong effect,
fast (15 sec)
 Overdose
 Scar tissue/
collapse of veins
 Infections
…What else impacts Efficacy of a drug?
Weight
Circadian cycle
Genetic Makeup
Drug
Efficacy
Age
Food Intake
loratadine
(Claritin)
Aspirin
Polypharmacy
Sunlight
Immune system
~12 meds
Very Important
Site of Action
BBB: lipid-solubility
Quick distribution
Ex: Morphine vs Heroin
= efficacy but….
Varying site of action for the same effect
Ex: Morphine vs Aspirin  Analgesic
suppresses neurons
increases chemical
Depressants, Sedatives, Anxiolytics
Alcohol
Barbiturates
Benzodiazapines
Alcohol (ethanol)
 small & lipophillic
 Depressant
Mod-Hi
Low
Decrease Neuronal Firing
Stimulate neuronal firing
 Mod: Cog, perceptual, verbal motor impairment
 High: unconscious > 0.5 % death from respiratory
depression
Alcohol’s Immediate Effects on NT
GABA
Agonist
Sedation, incoordination
Glutamate
Antagonist
Memory loss & Cog
dysfunction
5HT
Antagonist Impulsiveness,violent behaviors,
sleepiness
Agonist
Reinforces alcohol habitat
DA
Dilation of blood vessels  red face
Urination  diuretic urine by kidneys
A) Alcohol stimulate the release of endogenous opioids
B) Endogenous opioids (e.g., beta-endorphin) are released into the
synapse
C) stimulate activity at opiate receptors, which produces a signal in
the target neuron
D) Exogenous opiates (morphine) stimulate opiate receptors
http://www.youtube.com/watch?v=wDcyBXJAZNM
Alcohol (ethanol)
 Korsakoff’s Syndrome: memory loss
sensory motor dysfunction, dementia
Binges: no Vitamins…carbohydrates
Brain damage due to thiamine (vitamin B1)
Brain needs thiamine to metabolize glucose
Shrinkage of neurons Mamillary bodies, Hippocampus
Depressants, Sedatives, Anxiolytics
Barbiturates
Benzodiazapines
Barbiturates:
Sedation
Sleep inducing
Anesthesia
Muscle relaxant
(0ld drug: 1903)
Phenobarbital  anticonvulsant
Pentobarbital
Indirect agonist  GABA
the duration of CL- channels (hyperpolarize)
“Drugged” next day…reduce respiration
Replaced by BENZODIAZEPINES
Benzodiazepines:
First BZ patented in 1959
 Chlordiazepoxide (Librium)
 greater muscle relaxant properties vs respiratory effect
 anxiolytic
Indirect agonist  GABA
BARBITS:
the duration of CL- channels (hyperpolarize)
BZ:
the frequency of CL- channels (hyperpolarize)
Diazapam (Valium) - No “Drugged” next day
Alprazolam (Xanax)
Indirect Agonist
Psychostimulants
Cocaine
Amphetamine
Caffeine
Cocaine
 local anesthetic and CNS stimulant
 coca bush
 lipid soluable
Behavioral Effects:
•euphoria
•excitement
•reduced hunger
•a feeling of strength
• friendly, outgoing
Neurological and Behavioral problems:
•dizziness
•headache
•movement problems
•anxiety
•insomnia
•depression
•hallucinations
Caudate Nucleus
VTA
Nucleus Accumbens
Cocaine concentrates especially in the reward areas. Cocaine
accumulation in caudate nucleus can explain other effects such as
increased stereotypic behaviors (pacing, nail-biting, scratching, etc).
Cocaine
 Agonist of Catecholamines
Blocks reuptake of DA, Norepi,
Epi to presynaptic terminal
PNS: constricts of blood vessels
dilation of pupils
irregular HB
Reuptake pumps
DA
Cocaine
DA receptors
PET Scan
red = high use of glucose
yellow = medium use
blue = least use of glucose
cocaine user do not use (metabolize) glucose as effectively as
the brain of the normal person = Risk of Stroke & Epilepsy
D2 Receptors in Monkeys
Cocaine – Environment alters
receptors
Subordinate
Subordinate
Dominant
Dominant
Patient died of an overdose of cocaine – DA constricts brain vessels
• small lesions
- cell death, or strokes
•acute hemorrhages
- can happen in heart =
•hypoxia (lack of oxygen)
infarction or attack (sudden death).
Psychostimulants
Amphetamine
Caffeine
Amphetamines (stimulant):
http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swf
CNS & Sympathetic NS (asthma, sleep disorders)
1. cause the release of dopamine from axon terminals
2. block dopamine reuptake
3. inhibit the storage of dopamine in vesicles
.
dextroamphetamine, benzedrine, and Ritalin
Short-term effects:
•Increased heart rate
•Increased blood pressure
•Reduced appetite
•Dilation of the pupils
•Feelings of happiness and power
•Reduced fatigue
CAFFEINE
- most popular drug in the world
-coffee, tea, cocoa, chocolate, some soft drinks,
& drugs
- coffee bean, tea leaf, kola nut and cocoa pod
- Pure caffeine is odorless and has a bitter taste
•increase alertness
•reduce fine motor coordination
•cause insomnia
•cause headaches, nervousness and
dizziness
www.youtube.com/watch?v=JP7EQ6e5d1c
What NT does caffeine affect:
Adenosine
• inhibitory of synaptic transmission
Caffeine antagonist of Adenosine
Increase firing of cortical neurons & locus
coeruleus (regulator of arousal & vigilance)
(RAS)
http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swf
Caffeine also:
increase heart rate, constrict blood vessels, relax air
passages to improve breathing and allow some muscles to
contract more easily
Massive Doses: Fatal!
10 grams  80-100 cups of
coffee in rapid succession
(U.S. = avg. 100g/yr)
160mg
Coffee: 60-150 mg
Coca-Cola: 46
Pepsi: 38
Chocolate: 1-35
(U.S. = 200-300mg/day)
Vivarin, Excedrin, Dextrim, Dristan, No Doz
Marijuana
"We now know that marihuana –
•Destroys will power, making a jellyfish of
the user. He cannot say no.
•Eliminates the line between right and
wrong, and substitutes one's own warped
desires or the base suggestions of others
as the standard of right.
•Above all, causes crime; fills the victim
with an irrepressible urge to violence.
•Incites to revolting immoralities,
including rape and murder.
•Causes many accidents, but industrial
and automobile.
•Ruins careers forever.
•Causes insanity as its specialty.
•Either in self-defense or as a means of
revenue, users make smokers of others,
thus perpetuating the evil."
1930’s
Reefer Madness!!!!!
H. Anslinger (1930’s) FBN
•Brain damage
•Criminal behavior
•Insanity
•Sexual perversion
Marijuana (cannabis sativa)
• Dried leaves and flowers cannabis plant
• Contains over 400 different chemicals
• 60 are cannabis
Delta 9-Tetrahydrocannabinol (THC)
• 1 joint = 10 to 20 mg of THC
• Inhalation  Lungs Brain (BBB)
• Lipid soluable: weeks in system
2 Receptors (1988)
CB1
GPCR’s
CB2
Brain regions in which cannabinoid receptors are abundant
Cerebellum
Body movement coordination
Hippocampus
Learning and memory
Cerebral cortex, especially
cingulate, frontal, and
parietal regions
Higher cognitive functions
Nucleus accumbens
Reward
Basal ganglia
Movement control
moderately concentrated
Hypothalamus
temp reg, salt, water balance,
reproductive function
Amygdala
Emotional response, fear
Spinal cord
Peripheral sensation, pain
Brain stem
Sleep, arousal, temp reg, motor
control
Central gray
Analgesia
Nucleus of the solitary tract
Visceral sensation, nausea
vomiting
Localization of THC Binding Sites
VTA, nucleus accumbens, caudate nucleus,
hippocampus, and cerebellum
THC affects two neurotransmitters:
Dopamine & GABA levels may also be altered
Dopamine
GABA
Dopamine
Dopamine Receptor
Why do we have these receptors?
Anandamide (1992): endogenous THC!
(just like "endorphin" is the brain's own morphine)
• binds to THC receptors
• is synthesized from lipid, a fat-like material
in the cell membranes – not made in terminal!!!
• Synthesized in the hippocampus, thalamus, cortex, striatum,
lowest in the cerebellum, pons and medulla
• Important signal early in development: embyro to uterus wall
Why would we have a chemical in the brain that
disrupts short-term memory??
Anandamide may be involved in eliminating unneeded information
from memory
• Anandamide discovered in chocolate
• slows the destruction of chemicals that
activate marijuana's receptor in the brain
Use of Marijuana for Chemo Patients
Vomiting: 5 HT3 receptors
in raphe nucleus
Medicinal Purposes
Serotoninergic
THC binds 5 HT3  anti-emetic
(anti vomiting)
MARINOL® (dronabinol): synthetic
version of a naturally occurring delta-9THC: Anandamide Agonist
Heroin
Heroin (Opiate)
•Analgesia (reduced pain)
•Brief euphoria (the "rush" or feeling of well-being)
•Nausea
•Sedation, drowsiness
•Reduced anxiety
•Hypothermia
•Reduced respiration; breathing difficulties
•Reduced coughing
Heroin (Opiate)
•Derived from sticky resin of opium poppy
•Raw opium is morphine  heroin
•Opiate receptors
•Endogenous ligand  endorphins
Periaqueductal Gray  analgesia
Reticular formation  sedation
Preotic area  hypothermia
VTA & Nucleus Accumbens  reinforcement
Heroin crosses through the BBB 100 X faster than morphine
because it is highly soluble in lipids = addictive
Opiate Receptors
Endorphins (endogenous ligand)
feel-good chemicals naturally-manufactured in the
brain when the body experiences pain or stress
They are called the natural opiates of the body