2009 - lecture 8 artificial & natural ligands: drugs
TRANSCRIPT
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2009 - Lecture 8
Artificial & Natural Ligands:Drugs
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VikingsAmanita Muscaria
GABA agonist
EgyptiansBeer
DA & GABAAgonist
5HT & GlutamateAntagonist
American IndianPeyote
5HT & DAagonist
ChineseTea
Stimulant
Drugs have been used for centuries
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Animals self administer ETOH coca leaf
Not just humans…
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Everybody takes drugs!..in one form or anotherDRUG USE = Ubiquitous
7 out of the 10 of leading causes of disabilities in US
Drug Use
Major depression
Schizophrenia
Manic Depressive Illness
OCDDementia
Degenerative CNSDrug Abuse
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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
National Surveys
Soci
ally
acc
epta
ble
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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.
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College Students
YEAR 93 94 95 96 97 98 99 00 01 02 03
Marijuana 27.9 29.3 31.2 33.1 31.6 35.9 35.9 35.2 34.0 35.6 33.7 %
Cocaine 2.7 2.0 3.6 2.9 3.4 4.6 4.6 4.8 4.7 4.8 5.4 %
Source: University of Michigan, Monitoring the Future National Survey Results on Drug Use, 1975-2003, Volume II: College Students, 2004.
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Percent of College Students/Young Adults Using Marijuana,2003–2004
College Students Young Adults
2003 2004 2003 2004 Past month
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
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
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Total number of drug mentions in drug abuse-related emergency department visits, by type of drug, 1999-2002
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
New phenomena:
Baby boomer overdosing
197022 yrs198532 yrsNow 43 yrs
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What is a drug?
Chemical that alters one or more normal biological processes
Psychoactive, Psychotropic
Alter behavior, cognitive function or emotions
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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
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Tolerance:
state of decreased sensitivity to a drug as a result of continued exposure to it
Takes more drug to get the same affect
dose
effe
ct
Dose response curve: shift to the right
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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
Tolerance???compensatory mechanisms that oppose the
effects of the drug
VERY IMPORTANT!!!Setting: Social, physical environmental
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Seigel et al. (1982)Tested the hypothesis that setting is important in drug tolerance
Heroin can be conditioned to the environment
Group 1 Group 2 Group 3
30 days of heroin in varying environments
Heroin (colony) Placebo (colony) Placebo (colony)Placebo (noisy room) Heroin (noisy room) Placebo (noisy room)
Colony noisy room colony noisy room colony noisy room
All animal injected with lethal dose (15mg/kg)
96% diedOnly 32% died
64% died
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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
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Classical Conditioning Model: Heroin Overdosing
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Tolerance???compensatory mechanisms that oppose the
effects of the drug
Effects of heroin
Heroin withdrawal symptoms
euphoria dysphoria
constipation diarrhea & cramps
relaxation agitation
Withdrawal symptoms are compensatory reactions in the body that oppose the
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Psychopharmacology:
Study of drugs on NS behavior
What Determines Drug Efficacy?
PHARMACOKINETICS
Absorbed bloodstream Distributed bloodstream Metabolized broken down Eliminated Urine, sweat feces, mother’s milk
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routes of administration
Absorbed IV Distributed IP Metabolized IM Eliminated PO
SublingualSite of Action inhalation
Pharmacokinetics
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Swallowed Stomach (enzymes) bloodstream Intestine (alcohol) Liver
Bloodstream
Unpredictable & time consuming
PO: Most common, easiest, safe, cheapest
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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 IV: Strong effect,
fast (15 sec) Overdose Scar tissue/ collapse of veins Infections
IM: Muscle more rapid/PO hurts!!
…What else impacts Efficacy of a drug?
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Drug EfficacyAge
Sunlight
Genetic Makeup
Weight
Circadian cycle
Food Intake
Immune system
Polypharmacy
loratadine(Claritin) Aspirin
~12 meds
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Very Important
BBB: lipid-solubilityQuick distribution
Ex: Morphine vs Heroin= efficacy but….
Site of Action
Varying site of action for the same effect
Ex: Morphine vs Aspirin Analgesic suppresses neurons increases chemical
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Depressants, Sedatives, Anxiolytics
AlcoholBarbiturates
Benzodiazapines
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Alcohol (ethanol) small & lipophillic
Depressant
Mod: Cog, perceptual, verbal motor impairment High: unconscious > 0.5 % death from
respiratory depression
Mod-Hi Decrease Neuronal Firing
Stimulate neuronal firingLow
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GABA Agonist Sedation, incoordination
Glutamate Antagonist Memory loss & Cog dysfunction
5HT Antagonist Impulsiveness,violent behaviors, sleepinessDA Agonist Reinforces alcohol habitat
Alcohol’s Immediate Effects on NT
Dilation of blood vessels red faceUrination diuretic urine by kidneys
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A) Alcohol stimulate the release of endogenous opioidsB) Endogenous opioids (e.g., beta-endorphin) are released into the
synapse C) stimulate activity at opiate receptors, which produces a signal in
the target neuronD) Exogenous opiates (morphine) stimulate opiate receptors
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Alcohol (ethanol) Korsakoff’s Syndrome: memory loss sensory motor dysfunction, dementia
Binges: no Vitamins…carbohydratesBrain damage due to thiamine (vitamin B1)Brain needs thiamine to metabolize glucose
Shrinkage of neurons Mamillary bodies, Hippocampus
http://www.youtube.com/watch?v=wDcyBXJAZNM
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Depressants, Sedatives, Anxiolytics
BarbituratesBenzodiazapines
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Barbiturates: (0ld drug: 1903)
Sedation Phenobarbital anticonvulsant Sleep inducing PentobarbitalAnesthesiaMuscle relaxant
Indirect agonist GABA
the duration of CL- channels (hyperpolarize)
“Drugged” next day…reduce respiration
Replaced by BENZODIAZEPINES
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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 dayAlprazolam (Xanax)
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Indirect Agonist
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Psychostimulants
CocaineAmphetamine
Caffeine
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Cocaine local anesthetic and CNS stimulant coca bush lipid soluable
Neurological and Behavioral problems: •dizziness •headache •movement problems •anxiety •insomnia •depression •hallucinations
Behavioral Effects:•euphoria •excitement •reduced hunger •a feeling of strength • friendly, outgoing
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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).
Caudate Nucleus
Nucleus Accumbens
VTA
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Cocaine Agonist of Catecholamines
Blocks reuptake of DA, Norepi, Epi to presynaptic terminal
PNS: constricts of blood vessels dilation of pupils irregular HB
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Reuptake pumps
Cocaine
DA receptors
DA
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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
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D2 Receptors in MonkeysCocaine – Environment altersreceptors
Subordinate
Dominant
Subordinate
Dominant
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Patient died of an overdose of cocaine – DA constricts brain vessels• small lesions •acute hemorrhages•hypoxia (lack of oxygen)
- cell death, or strokes- can happen in heart = infarction or attack (sudden death).
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Psychostimulants
AmphetamineCaffeine
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Amphetamines (stimulant): http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swfCNS & Sympathetic NS (asthma, sleep disorders)
1. cause the release of dopamine from axon terminals 2. block dopamine reuptake3. 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
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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
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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)
Caffeine also:increase heart rate, constrict blood vessels, relax air passages to improve breathing and allow some muscles to contract more easily
www.youtube.com/watch?v=JP7EQ6e5d1c
http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swf
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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
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"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."
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Reefer Madness!!!!!H. Anslinger (1930’s) FBN•Brain damage•Criminal behavior•Insanity•Sexual perversion
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Marijuana (cannabis sativa)
• Dried leaves and flowers cannabis plant• Contains over 400 different chemicals • 60 are cannabis
Delta 9-Tetrahydrocannabinol (THC)
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• 1 joint = 10 to 20 mg of THC• Inhalation Lungs Brain (BBB)• Lipid soluable: weeks in system
2 Receptors (1988)
CB1 CB2
GPCR’s
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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
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Localization of THC Binding Sites
VTA, nucleus accumbens, caudate nucleus, hippocampus, and cerebellum
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THC affects two neurotransmitters: Dopamine & GABA levels may also be altered
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Dopamine
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GABA
Dopamine
Dopamine Receptor
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Why do we have these receptors?
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(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 (1992): endogenous THC!
Anandamide may be involved in eliminating unneeded information from memory
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• Anandamide discovered in chocolate• slows the destruction of chemicals that activate marijuana's receptor in the brain
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Use of Marijuana for Chemo Patients
Vomiting: 5 HT3 receptorsin raphe nucleus
THC binds 5 HT3 anti-emetic(anti vomiting)
Serotoninergic
MARINOL® (dronabinol): synthetic version of a naturally occurring delta-9-THC: Anandamide Agonist
Medicinal Purposes
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Heroin
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•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)
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Heroin (Opiate)
•Derived from sticky resin of opium poppy•Raw opium is morphine heroin•Opiate receptors•Endogenous ligand endorphins
Heroin crosses through the BBB 100 X faster than morphine because it is highly soluble in lipids = addictive
Periaqueductal Gray analgesiaReticular formation sedationPreotic area hypothermiaVTA & Nucleus Accumbens reinforcement
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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