2009 - lecture 8 artificial & natural ligands: drugs

2009 - Lecture 8

Artificial & Natural Ligands:Drugs

VikingsAmanita Muscaria

GABA agonist

EgyptiansBeer

DA & GABAAgonist

5HT & GlutamateAntagonist

American IndianPeyote

5HT & DAagonist

ChineseTea

Stimulant

Drugs have been used for centuries

Animals self administer ETOH coca leaf

Not just humans…

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

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

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 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.

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

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

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

Takes more drug to get the same affect

dose

effe

ct

Dose response curve: shift to the right

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

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

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

Effects of heroin

Heroin withdrawal symptoms

euphoria dysphoria

constipation diarrhea & cramps

relaxation agitation

Withdrawal symptoms are compensatory reactions in the body that oppose the

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

routes of administration

Absorbed IV Distributed IP Metabolized IM Eliminated PO

SublingualSite of Action inhalation

Pharmacokinetics

Swallowed Stomach (enzymes) bloodstream Intestine (alcohol) Liver

Bloodstream

Unpredictable & time consuming

PO: Most common, easiest, safe, cheapest

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?

Drug EfficacyAge

Sunlight

Genetic Makeup

Weight

Circadian cycle

Food Intake

Immune system

Polypharmacy

loratadine(Claritin) Aspirin

~12 meds

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

Depressants, Sedatives, Anxiolytics

AlcoholBarbiturates

Benzodiazapines

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

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

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

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

Depressants, Sedatives, Anxiolytics

BarbituratesBenzodiazapines

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

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)

Indirect Agonist

Psychostimulants

CocaineAmphetamine

Caffeine

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

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

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

Cocaine

DA receptors

DA

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 MonkeysCocaine – Environment altersreceptors

Subordinate

Dominant

Subordinate

Dominant

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).

Psychostimulants

AmphetamineCaffeine

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

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

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

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 CB2

GPCR’s

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?

(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

• 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 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

Heroin

•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)

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

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