"drugs and behavior" syracuse university lecture notes

8/12/2019 "Drugs and Behavior" Syracuse University Lecture Notes

http://slidepdf.com/reader/full/drugs-and-behavior-syracuse-university-lecture-notes 1/24

Biological Bases of Behavior

The nervous system and its role in psychopharmacology1. From the behavioral effect of the drug, infer structures involved.2. Classification of drugs based on their effects on the nervous system

(sympathomimetics)3. Pathology of a known structure (as in Parkinsonism [lack of dopamine])

search for new drugs

Neuron = nerve cell“Soma” is cell body

3 Types: Sensory, Motor, Inter-NeuronNerve = Bundle of axons in the peripheryTract = bundle of axons in the central nervous systemGanglion = collection of neurons in the peripheryNucleus = collection of neurons in the central nervous system (controls biological

drives)

Neurons communicate by electrical signal along axons and chemical means at end ofaxons.The inside of an axon is negative as opposed to the outside (-65 - -70millivolt)……………….resting membrane potential When the axon is excited, the inside becomes positive compared to the outside (+40millivolt)

Resting membrane potential is when neuron is at rest.Hypo polarization is the slight increase; failed initiation

Resting potential Depolarization Action Potential Hyperpolarization Refractory Period Resting potential

Ions on outside of cell - Sodium, Potassium, Chloride------sodium channel---potassium ch--------------------- Semipermeable membraneIons inside of cell - Sodium, Potassium, less Chloride, N ionA- = N ion

Action potentialWhen you excite the cell, the inside of the cell becomes depolarized.

Sodium channels open. Inside becomes more positive. Electrical force and fusion

force propel Sodium.Potassium channels open, k flies out of cell after further depolarizationAt peak of action potential, sodium channels close and more potassium channelsopen. K slowly close, but K keeps flying out of cell, leading to hyperpolarization andrefractory period.



Major Divisions of the Nervous SystemPeripheral CentralSpinal Spine

Somatic (activates muscle, control)Cranial Brain

Autonomic (activates organ, no control)Sympathetic (excites you) vs. Parasympathetic (calm you)starts in middle of spinal cord in beginning and end of spinal cordGanglia [pre,post]: short, long long, shortCentral Nervous System is slower

Post ganglionic portion is muscarinicFunction of spinal cord: Reflex, ascending and descending tracts

Type of reflexes: monosynaptic reflex, disynaptic reflex, polysynaptic reflexes

BrainHindbrain

-Medulla: biological reflexes-Pons: cross-over-Cerebellum: balance and modulatory function

Midbrain-Tectum: vision and hearing (feedback)-Tegmentum:

reticular formation, wakes up brain

substantia nigra, dopamine is made hereventral tegmental area, dopamine is made here also

Forebrain-old

hypothalamus: detects elements in blood, responsible for biologicalmotivationthalamus: everything goes thru hear, sight, sound, smell, etcbasal gangli: smooth movementslimbic system (amygdala, cingulate, septum, hippocampus): emotions

hippo - memorycingulate and septum - regulate impulses

amygdala - fear and aggressionMedial Forebrain Bundle: dopaminergic system reaches into nucleusaccumbensNucleus Accumbens: pleasure

-newoccipital lobe: visual areaparietal lobe: sensory associationfrontal lobe: thinking, reasoning, consciousness



temporal lobe: hearing area, advanced visual processing, memoryprimary sensory and motor areasBroca’s area: speech production area, thinking about language Wernicke’s area: speech comprehension

Correlates of Drug Action

Electro-chemical communication: the synapse-axon, pre-synaptic terminal, synaptic knob-synaptic vesicles, receptors, enzymes, neurotransmitters

Otto LoewiStimulated Vagus nerve, then take fluid from heart A to heart BVagus Stoff is acetylcholineHeart B slows down the same as ADemonstrated same effect with liver, and found it is same for all organs

Sequence of events at a synapse

Neurotransmitter Criteria1. Identification2. Mechanism for synthesis; enzymes or pre-cursor in cell3. Release and collection4. Mechanism for termination5. Application: agonist vs antagonist

Qualifiers- Acetylcholine (ACh)- Seratonin (SE)

- Dopamine (DA)- Noradrenaline (Norepinephrine) NA (NE)- Gamma amino butyric acid (GABA)- Endorphins, glutamate, aspartate, glycin, peptides

The Cholinergic Synapse- Choline, coenzyme A, acetyl group- Acetylcholine: two types of receptors

Fast-acting cholinergic receptorSlow-acting cholinergic receptor

- Nicotinic vs Muscarinic (nicotine, mushrooms)Agonists: Nicotine, Muscarine

Antagonists: Curare, AtropineEnzyme: Acetylcholine Esterase (AChE)Antagonist: Physostigmine (ESERIN)

How it works, what it does? In relation to acetylcholine.

Acetylcholine as transmitterSkeletal muscles at neuromuscular junction

- Agonist: Nicotine



- Antagonist: CurareAutonomic Nervous SystemSympathetic: pre-ganglionic only, Nicotine vs CurareParasympathetic: pre and post ganglionic

-in pre, Nicotine vs curare

-in post Muscarine vs atropine

Central Nervous SystemSpinal cord (the RENSHAW cell; inhibitory neuron. When a motor

neuron fires, it sends collateral to RENSHAW and in turn is in inhibited. Preventsoverfiring) Nicotinic

Brain: Tegmental Reticular Formation : muscarinicBrain: amygdala, septum, hypothalamus, cortexAcetylcholine is involved in mediating aggression, drinking, motor

behavior, and learning

The Serotonergic Synapse

Tryptophan (tryptophan hydroxylese) [precursor to making serotonin]5-HTP (Dopamine Beta Oxidase)5-HT = SerotoninTurkey meat has lots of tryptophan

Enzyme: mono-amine-oxidase (MAO), diffusion and reuptake. Breaks downserotonin, dopamine, and noradrenaline.

The effects of:- Reserpine, LSD, Prozac, Iproniazid

Used in combination to find outcome (question on test)

Serotonin as transmitter:- In the periphery, smooth muscles (gut)- In the brain: AH (shivering), RF slow wave sleep (PCPA), Limbic System

(mood), cortex (hallucinations = too much serotonin)Dopaminergic Synapse

- Phenylalanine (Phenylalanine hydroxylase)- Tyrosine

- DOPA- Dopamine (MAO, COMT)

Valentine Video on Dopamine- Acts as as inhibitor like Serotonin- Travel through the Vasal Ganglia, controlling movements- Low amounts of dopamine cause schizophrenia, but don’t know why

‘pleasure chemical’ - Love is a drug (dopamine rushes into the brain when one falls in love)



- Noradrenaline is also part of love- Oxytocin is the chemical released during sex, strengthens family bonds

and monogamy, “cuddle chemical”

Amphetamine, cocaine, imipramine

Amphetamines block reuptake for dopamineCocaine blocks reuptake mechanisms for dopamineMechanism of action by imipramine (tricyclic antidepressant) - blocks

reuptake of dopamine but not as efficiently as cocaineReserpine, chlorpromazine, iproniazid, tropolone

Chlorpromazine (anti-psychotic) blocks dopamine transmittersIproniazid is an MAO inhibitorTropolone interferes with COMT (enzyme that breaks down dopamine),

functions as an anti-depressant

Dopamine as transmitter: VTA (Ventral Tegmental area) and SN (Substantia

Nigra)SN

Brain: basal ganglia motor behaviorVTA

Forebrain cognitionHypothalamus regulationmedial forebrain bundle pleasure

L-Dopa is precursor to dopamineIf treated with L-Dopa for Parkinson’s disease, you may have hallucinations

similar to schizophrenics

If schizophrenics are given anti-psychotic medication, like chlorpromazine,side effects could include Parkinson like symptoms, lack of pleasure, and regulationis fucked up, including lactation

Noradrenergic synapsePhenylalanine, tyrosine, DopaDopamine (Dopamine beta oxidase)Noradrenaline (Norepinephrine)Everything else is same as for dopamine)

Noradrenaline as a transmitter in:Autonomic Nervous System

-Sympathetic post-ganglionicAdrenergic receptors

- two types of receptors: alpha and beta- Alpha: NE>EPI>Isoproterenol (vessels)- Beta: Iso>EPI>NE (heart)Alpha antagonist --- Phenoxybenzamine (blocks alpha receptors)Beta antagonize --- Propranolol (blocks beta receptors)Brain: RF (arousal), VMH [Ventral Medial Hypothalamus] (satiety, ex. food)



Noradrenaline initiates REM sleepAmphetamines stimulate VMH, therefore no appetite

Brain: noradrenaline is needed for general activity level

The GABA-ergic synapse

Glucose (supporting tissue) Glutamate, glutamine [not charged, can enter cell], (glutaminese transforms

it back to glutamate)Glutamate (GAD - vitamin B6)\

Gamma Amino Buteric AcidGABA (GABA-T)

FUCK

Behavior DisordersPsychosis

-what is mental illness?-myth (Thomas Szasz)

Mind cannot be sick, only organCan be biologicall sick

-brain pathologyPsychosis: organic vs. functional (misnomer)Process: overtimeReactive: (couple weeks)

SchizophreniaSplit-brain

The split associations, affect, ambivalence, autism

Etiology of schizophreniaCause (mechianism)

1. Psychosocial theories2. Biochemical approaches

a) genetic factorsb) environmental stress (also viruses)c) interaction theories

Concordance rate (gottesham + Shills 1972)Severe 77----15 = 62%

Mild 27-----10 = 17%

Vulnerability HypothesisFive to 6 genes, related to neural connections and neurotransmitter are involvedA threshold event elicits the illness

Uterine (development factors - winter babies)Head injuriesDrug abuse



Starvation

Fundamental symtpoms: thought, affect, autism, hallucinations, delusionsTypes:

-simple (disorganized) - hobos

-catatonic - waxy flexibility: don’t move -paranoid - delusion

Positive + negative symptoms-positive: agitated speech, cognitive and affective dissociation, hallucinations,

delusions-negative: reduced affect, autism, waxy flexibility

TheoriesTransmethylation hypothesis: metabolic errorDopamine hypothesis: excess DA in forebrain

-support LDA antagonist, potency, agonists, l-dopa effects

Chloropromazine, DA blockingRelates to efficacyAmphetamine ffetsHarvard study - can’t differentiate from speed

Disregulation hypothesis-involvement of SE

clozapine (Clozonl) D2 and 5HTZ block

PCP mood

Hypo-glutaminergic modelBlocks glutamateGlutamate excites GABAIf no GABA inhibitionExcess dopamineGlutamate’s role in cognition Hippocampus

Two-factor model: positive(DA) vs. negative (brain damage, ventricles, tissue)hypofrontality (reduced prefrontal activity)

Treatment-psychosurgery-psychotherapy-pharmacotherapy-history

Laborit, Chartentien, delay 1952



Chlorpromazine (Thorazine)DA blocker - not effective with negative symptomsSide effects: extra pyramidal effectsTardine dystension

Extrapyramidal effects-Parkinsonism 20-30%-Dystonia - 16-25%Akathisia - 20-40%

Affective DisordersDepressionManiaTerminology: endogenous vs reactive

Unipolar vs polarDefinition number symptoms for particular duration

No criteria of affective disorders it is a label.Two dimensions: severity, durationMania: 3 symptoms for at least 1 week (restlessness pressured speech, flight ofideas, conceit, no need to sleep, inattention)Depression: 4 symptoms at least for 2 weeks (dysphoria, hopelessness irritability,appetite + or - weight, sleep, energy, lack of concentration, suicide, etc.)

Mood disorders and TreatmentMajor depressive disorder (recurring episodes)Dysthymic disorder (lower grade, longer duration)

Cyclothymic disorder (bipolarity over long period)Seasonal affective disorder

Etiology of DepressionGenetic:

Concordance rate 72% vs. 14% (Amish) [identical twins vs fraternal]Biochemistry:

Changed level of neurotransmitters (chicken or the egg problem) ReserpineReserpine decreases neurotransmitter levelsNeurotransmitter reduction can lead to depression

Environment:

High stress, death, abuse (physical, sexual)Loss of job, illness

Theories of DepressionPsychodynamic e.g. Freud (loss, blame, guilt, aggression)Behaviorist - reinforcement loss

-operant sympathyCognitive model of depression



-negative schemaall observation is negative. Explanation only works if there arenot problems biologically or physically

Biogenic amine hypothesisBio-behavioral interpretation

When a situation is stressful, affects biochemistry, thus creating depression.Chemistry of brain causes depression, but environment can cause the changein the brain-learned helplessness: dog in cage. Cage had grid floor. Light would go on for

10 seconds, then dog was shocked. After half an hour, repeated. After a few trials,the dog sat in the corner of the cage and took the shock without moving. He thenopened the cage, and the dog still sat there and took the shock.

-interpersonal stress: transferred dominant primate to group of monkeysand he lost his dominance. He sat by himself without interacting with the othermonkeys. Began self-medicating with alcohol.

-frustration: parents forcing kid to go to medical school, but kid cannot

complete the work and leads to frustration and then depression.-punishment: not just physical. losing job, etc.-combat loss: two mice together usually ifght to death. Before they kill each

other, separate them. The winner had a high testosterone level; the loser’s was

lower. In humans, two guys played tennis. After the match the loser had much lowerfrom baseline while winner had higher.

The Treatment of DepressionECT 80%. Only used if all other attempts have failed. Single most effective method,but used sparingly.Spontaneous improvement 20-25%

Placebo 25-60%Anti-depressants 50-75%Trans-cranial-magnetic-stimulation (TMS) FDA approved: Electro-current passedthrough brain without convulsions. Useful for patients resistant to drugs.

Anti-depressantsMAO inhibitors

-tranylcypromine (Parnate)-pargyline (Eutonil)-phenelezine (Nardil)

Tricyclic antidepressants

-imipramine (Tofranil)-amitriptyline (Elavil)

New Generation anti-depressants-Fluoxetine (Prozac)-Sertraline (Zoloft)-Paroxetine (Paxil)-SNRI’s (Effexor)



MAO inhibitorsHistory: ECT 1950, isoniazid, iproniazid 1952 Jean DelayIsoniazid was intended to treat tuberculosis, but instead just developed good moodsFate: Affinity to MAO enzyme, 98% excreted via urine in 24 hours, peak plasma 1hour. Effects not instantaneous, takes a few days for antidepressant effects to kick in

Drugs presently used:-tranylcypromine (Parnate)-pargyline (Eutonil)-phenelezine (Nardil)

brought in young woman who jumped from 4th floor, broke hips trying to commitsuicide. She was under observation and given MAO inhibitors, which helped herrespond to people around her because previously she ignored any therapeutics.Mechanism of action:

-interference with MAO-increase biogenic amines

Behavioral effects:

-animal: pressor, tremors-human: increased blood pressure

Side effects:-suicide, agitation-brainstorm, convulsions-drug interactions - toxicity-diet interactions - hypertension-insomnia, restlessness, fatigue, confusion

TricyclicsHistory: CPZ 1948, imipramine (Tofranil) 1958, Kuhn

Mechanism: block reuptake of NE, SE, DA-antiemetic, synergistic with CPZ-atropine like side effects (e.g. dry mouth)

Amitriptylene (Elavil) anti-anxiety as wellNortriptylene (Norpramine) lack of driveTrazodone (Desyrel) less side effects

SSRI (selective serotonin reuptake inhibitors)Fluoxetine (Prozac)

-marketed in 987-its appeal is convenience

-safe for: depression, anxiety, eating disorders and OCDSertralin (Zoloft)

-shorter half-life, diarrheaParoxetine (Paxil)

-most potent, least side effects, drowsiness, dry mouth, loss of sex drive

ManiaHypomania (surge of energy, optimism, racing thoughts, unrealistic expectations)



Mania (same as above, plus irritability and aggression)Difference in intensity of symptomsModerate

Theories of Mania

Organic Brain Disorder-epileptiform anxiety-tumors, virus, drugs, prions (capable of replicating. Combine with naturally

occurring proteins and make them more like themselves. Mania is a result of this)Biogenic Amine Hypothesis

-noradrenaline

Treatment of ManiaLithium Salts

-Cade (1949) ureate, carbonate-Mono-valent cation, no metabolism

-Plasma concentration = brain conc.-Half dose excreted in 24 hours

LithiumMechanism of action:

-30% higher NE reuptake-Inhibit sodium dependent processes-Inhibits enzyme GSK-3

Behavioral effects:-sedation, ataxia, fatigue, nausea, diarrhea, slurred speech

More Recent ApproachesCarbamazepine (Tegretol)

-blocks sodium channels-inhibits enzyme activity-good alternative to lithium-inhibits GSK-3

Valproic Acid-inhibits GABA-T-Both have side effects, sedation, lethargy, including teratological effects

Stimulants

Amphetamines-d-amphetamine (Dexedrine)-dl-amphetamine (Benzedrine-dl-amphetamine (Methedrine)

-3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy)History:

-Ephedra - horse tail plant MA-HUANG-Ephedrine - China 5000 year old remedy



-Akita Ogata 1919, Allas 1927 medicine-bronchodilator, analeptic, cardiovascular stimulant

Fate:-readily absorbed, 30 min oral, 5 min injection, single dose eliminated in 72

hours, 50% excreted unchanged

Mechanism of Action:-Block NE, DA reuptake-Release NE, DA and release more-MAO inhibitor

Pharmacological properties:-autonomic stimulant: ups Blood Pressure, Heart Rate, causes pupil dilation-spinal cord: facilitates reflexes-brainstem: analeptic-hypothalamus: stimulates satiety

Behavioral effects:-animal: spider’s web, firefly glow, chicks tweet, rats active

-human: Critical Flicker Frequency, Time Estimation Production,Wakefulness, alertness, concentration, confidence, euphoria, anorexia, athleticperformance, tremor, agitation, seizures. REM postponed 2 months reboundApplications:

-analeptic, anorexic, fatigue, depression, narcolepsy, ADDAbuse:

-speed: methamphetamine in various forms: eg. CrystalSpeed Ball: heroin and meth, heroin and cocaineKrystal: PCP or angel dustOther names: snug, bug, racerSide Effects:

-tolerance (different rates for) anorexia, arousal, euphoria-dependence and withdrawal symptoms (e.g. depression, fatigue)-psychosis, attention deficit, abuse “speed kills”

Review::

HypochondriasisConversion disorder symptoms hysteric dysfunction prognosis fair causeanxiety/traumatic episodeOCD prognosis good cause anxiety/frustrationPhysiological reactions for stress: hr, bp, rr, pupil size, dry mouth

Hans Selye, General Adaptation Syndrome

Alcohol- 20% stomach 80% small intestine

ALDH Aldehyde (Asians)Fetal Alcohol Syndrome - smaller brain, wide forehead, downsyWernicke’s Syndrome, Korsakoff’s Syndrome, Wikler reinforcement model



Congeners (aldehydes, alcohol, esteraseAbsynthe ingredients: thujone (wormwood)Paradoxical effects when using cocaine and amphetamines with alcohol

Sedatives

Barbiturates made from urea and malonic acidPhenobarbital = luminolMechanism of ActionAnxiolytics: propanediols & benzodiazepines

Diazepam (valium)Flunitrazepam (rohypnol) roofiesGHB, henri laborit. What is it used for?

The PCP modelHypo-glutaminergic modelBlocks glutamate

Hypofrontality - reduced prefrontal activityChlorpromazine = thorazineCauses tardive dyskinesia - 10-15% up regulation

Mood disorders0najor depressive disorder

ProzacTreatment of ManiaGenetic name, trade name, brand name differences

How do we make drugs into saltsSame thing (if you have an alkaline put it in acid)Examples of seven categories listedQuestion from appendix, scheduling of drugsSimilarities between symptoms of anxiety reactionsApplication of some anti-anxiety drugsLearned helplessnessDifferent categories of anti-anxiety drugsBlood alcohol LevelMechanism of action of alcoholFetal alcohol syndrome

Synthesis of alcoholFetal alcohol syndromeSide effects of barbituratesBarbiturates 3Symptoms of psychosisExtra-pyramidal symptoms 3LithiumTreatment of psychosis



From the reading of article, about Shaffer 2Theories of schizophrenia 2Henri LaboritFried article in student manual 2Various forms of depression

Prototypes of categories of psychoactive drugsBarbiturates and mechanism of actionAnti-anxiety drugs, how they workAnti-anxiety drugsSymptoms of psychosis 2Various forms of schizophreniaTheories of schizophreniaAnxiety disordersWickler’s model of addiction AbsintheMechanism of action of benzodiazepines

RohypnolGhbPrionsQuestions from appendix 2

AmphetaminesDOM (dimethoxy-4-methmphetamine)

-mega hallucinogen (trip last for three days)-Dow Chemical 1964 (5-10mg like mescaline)

Methylphenidate (Ritalin)-treatment for ADDD

-ADD due to low DA levels 15-30mg 4-5 times a day-Concern: growth, dependence, abuse

AdderallCombination of d-amphetamine and dl-amphetamine (Dexedrine-

Benzedrine)(saccharate, sulfate, -apartate, sulfate)These salts are metabolized at different rates-The Study drug-All aspects of abuse apply

AmphetaminesDesigner drugs: Phenylpropanolamine (PPA, Dexatrim, Hungrex)

MDMA - Ecstasy, XTC, Adam, Essence, Clarity, EEE

History of MDMAGermany, 1914, Merck COUS Appetite ControlAlexander Shulgin 1968Dow ChemicalsAlerts psychiatrists



Legal until 1985 in Texas-London-California Raves

Potential Illegal ChemistrySassafras tree -Safrole extracted from root bark

Isomerization, oxidation, aminationMolecular formula C10H10O2

Dose: 70-150mg or 40mg in 30 min intervalLD50 = mice 97mg/kg, rats 47mg/kg, dog 18mg/kg, monkey 22mg/kgMechanism of Action

-Release 5HT-Block reuptake of 5HT-Reduce 5HT by blocking 5HTP conversion-Promotes oxytocin release

Behavioral effects:-Empathogen: emotional, sensual overtones

-Anxiolitic: reduces anxiety, no hallucination from normal dose, yesform higher dose-“married couples” got hold of the feeling of love again, Ann Shulgin

Side Effects:-seizures, resistance to infection is impaired-Cardiovascular danger, rebound anxiety, anorexia, insomnia, nausea,jaw tension-limited safety data, schedule I drug, depletes serotonin(questionable)

XTC Likes

-related substances: MDA, MMDA, similar to xtc-myristicine and elemicin; the latter found in nutmeg or mace, they causeblurred vision and emesis

KHAT (Catha edulis)-A shrub in East Africa, (Somalia)-The fresh leaves contain Cathinone-The locals chew it, smoke it, brew it, and the effects are similar toamphetamine but less potent

CATMethcathinone (CAT) Germany 1928Used as antidepressant in Russia

Michigan 1987 (Parke-Davis student)CAT made with ephedrine, Drano, epsom salt, battery acid, etc.Anticoagulant side effects

Angel Dust (PCP, Sernyl)Phenocyclidine: super weed, busy bee, mist, goon. Krystal bag, tic-tac-toe7 million users aged 15-254000 admissions/year, suicide, homicide



Introduced 1956 as anestheticClose relative of ketamine, also an anesthetic but lesser effectsMechanism of action

NMDA receptor antagonistIndirect action on DA

Possible mechanism for schizoid behaviorPotential brain damage

Pharmacological effesContact through skinLoss of bladder or bowel control21 days later still in substantia nigraLarge dose, coma, seizures, death

Behavioral effectsGrimacing, inability to walk“I am wired, I am superior” Prolonged use = memory deficits, psychosis

Cross dependency with cocaineSelf inject vs mescaline, cross inject with cocaineAnti-social behaviorBlocks DA reuptake, treat with vitamin C and valium

CocaineHistory:

Erythroxylon tree, Peru, BoliviaPart of the Inca culture 500ADAlbert Niamann (1834-1861)Mariani’s wife, Holmes, Freud

Extraction

Base, acid, base, acidCrack vs. cocaine

FatePoorly absorbed from gutPresent in plasma for 6 hoursDetectable up to a week in body, in hair hundreds of years

Mechanism of actionBlocks reuptake of DA, NE, SE

Pharmacological effects:Local anesthetic (novocaine)Blocks nerve conduction, vasoconstriction

Stimulates respiration, the CVS and heart muscle. Causeshyperthermia (pyrogenic - warmth feeling)

Behavioral effects:Stimulant: motor activity, aggressionParanoia, paranoid schizophrenia, depression

Side effects:Tolerance, dependence and withdrawal symptomsBusiness venture: 100$ billion, dehumanizing



Xanthines

Coffee -Tea-History of Tea: 2700 BC Chinese medicine

Han Dynasty (206 BC - 22 AD)Japanese tea ceremony 8th centuryChocolate-History of Chocolate: Aztec, Maya culture, 1502 Europe (Columbus), 1528

Cortez’s recipe (used vanilla to make chocolate taste better) FATEXanthines are alkaloids (basic)They are slightly soluble in waterTheir absorption rate is erraticThey have low affinity to protein, high lipid solubility, their distribution

complete

Half-life is 3-5 hours, peek blood is 30-60 min, 90% metabolized by liver,significant increase in urine output

Mechanism of action-Adenosine antagonism (slows down cell functioning)-Increased cell metabolism-Calcium release at muscles-Release NE, E (70-114% increase)

Pharmacological properties-Diuretic, increase muscle strength, relaxes smooth muscles (BM,

bronchii)-Increase gastric secretion and cardiac output

-Dilates blood vessels, but increase blood pressureCNS effects

-spinal cord: increase mono and polysynaptic reflexes-Medulla - stimulates respiratory and vasomotor centers and the

vagus nerve-Decreases heart rate-Cortex: aroused EEG

Behavioral effects-Animal research: increase activity, speed of response rate, sex,

consolidation of memory, no improvement of memory-Coolidge Effect (male hen fucks many hens, but tires of same ones)

-Human research: improves attention, enhances performance ofexhausting work, ETOH (depresses reaction time) depression of RT, no effect on IQor REM

-Target detection-Side effects: Death at 57mg/kg about 60 cups of strong coffee in a

200lb person. Restlessness, irritability, agitation, muscle twitches, headaches,convulsions

-Tolerance: dilation, diuretic effect



-Cross tolerance with tea, chocolate-Not mutanigenic or teratogenic

Caffeine, the most used drug in the worldMg contents of beverages: Coca cola 34; Pepsi 37; Dr Pepper 38; 7up 0Jolt 71; Mt Dew 55; Royal Crown 36; TAB 44; Sprite 0; Mello Yellow 54

Brewed Coffee 80-150; instant 50-110, decaf 3-10; tea 30-75;chocolate 5-15

Content of some Over the Counter drugs: Vivarin 200; Anacin 30; Nodoze100; Excedrin 65; Dexatrim 200; Caffedrin 250; Vanquish 33; Midol 32; Dristan 0

It is Cytochrome p450 that metabolizes coffee. Rate of metabolism isdifferent for everyone.

NicotineGanglionic stimulants:

-Nicotine (Nicotina Tabacum) from tobacco-Nornicotine ------^

-Lobeline (Lobelia Inflata) from LobeliaHistory

-isolated 1828 from leaves-completely clear when isolated, looks like water

Fate:-liquid alkaloid, rapidly absorbed from GI (gastrointestinal tract),

respiratory tracts, skin-Distribution: quick 10 seconds, 99% redistributes in hour, faster in

smokers-Accumulation: kidney, urinary tract, bladder, liver, and brain

Metabolism

Liver 90%, half life 2 hoursExcretion

Kidney, rate determined by acidity of urine-Stress determines acidity

-Diet: raisin, figs, lima beans are alkaline-Reduction in smoking-Oxidative metabolic cotidine-Menthol prevents it, half life up

Biophasic effects-parasympathetic: salivary gland (wet vs dry)-sympathetic: NE release--HR 75-95 beat/min

-muscles: ACH -- excite vs relax. Causes relaxation of musclesMechanism of action

-nicotinic receptors-MAO inhibitory components

Harman, nornicotine-Results in increase: DA, NE, SE

Behavioral effects



-animals: improves acquisition, state dependency, reinforce, straindifferences

-humans: .5-2mg nicotine in cigarette; 10% of it inhaled and absorbed,4mg toxicity, 60mg lethal dose. Increased HR and BP. Constriction of coronaryarteries.

Side Effects:Respiratory stimulation then failure, nausea, salivation then dry

mouth, abdominal pain, vomiting, diarrhea, convulsions.Tolerance develops in four weeks

Teratogenic effect

SmokingHistory: flue-cured tobacco, birth of the cigarette

-1850 200/min; 1881 5000/min, the cigarette machine;200,017,000/min

-4000 additional chemicals besides nicotine

-Tar: PCHC (polycyclic-hydrocarbon: metal ion, radioactivecomponents

-Carbon monoxide and dioxide-Ammonia, cyanide, formaldehyde, gases and burn products-Nicotine

Is it bad for you?-Tar: emphysema, bronchitis, cilial damage-CO: takes up 10% of hemoglobin. Leads to exhaustion.-Others: carcinogens (e.g. formaldehyde)

1938 first study linkage to cancer1954 second, 1964 label “maybe”, 1971 label “is”, 1986 passive smoke

(KOOP)1987 addictiveAddictive: presence of withdrawal symptoms

Slow HR, metabolism, hot temperature, needTolerance, compulsive use

Study:1 pack vs 2 packs

Results: 2x still births, 2/3x higher ailments, 2x death rate, in women3x death rate, pipe/cigar significantly lower

Smoking style, child development, How to stop?, are patches anygood?

The OpiatesThe narcotic analgesics

-narcosis (sleep)-analgesia (absence of pain)

Source opium poppy (Papaver Somniferum)Opium: codeine, morphine, heroin (diacetylmorphine)



History:-4000 BC Sumerians (joy plant)-300 BC Greeks were aware of effects-600 AD China-1000 AD Arabs, Turkey

Morphine discovered by Friedrich Serturner 1803Codeine isolated by Robiquet 1832Heroin made by Wright 1874

-“soldier’s disease” using morphine to alleviate pain, led to addiction -Baeyer Co markets heroin as alternative

Fate:-morphine is alkaline, poorly absorbed from GI tract-better from blood, lungs-peak brain level is in 30-60 min (only small amt crosses blood-brain barrier-metabolized via conjugation, 90% excreted within 24 hours-heroin===hydrolysis====monoacetylmorphine===hydrolysis===morphine

-3mg heroin = 10mg morphineMechanism of Action:

1. Enhances serotonin synthesis (SE up and analgesia; reserpine vsmorphine effect) Reserpine interferes with analgesic properties ofmorphine

2. Prevents noradrenaline release (sympathetic reaction down, BP, pinpointpupil)

3. Cell metabolism (inhibition of tolerance with antibiotics)4. Opiate receptors

Central Nervous System effects1. Nerve conduction: no effect

2. Spinal cord: Polysynaptic reflexes (sexual response)3. Medulla: depresses Respiratory Center, VasoMotorCenter, EmeticC, raises

CO2 threshold, stimulates Chemical Trigger Zone. Feel like throwing up,can’t.

4. Hypothalamus: inhibits temperature control, inhibits release of stresshormone ACTH (which stimulates adrenal gland to release NE), gonadalhormones (ovulation stops, less sex drive), release antidiuretic hormone(retain fluids).

5. CNS effects: Limbic system, amygdala threshold up6. Cortex: EEG slows, REM sleep slows down (dream less)7. Pharmacological properties: Emesis due to direct GI tract effect.

Contraction, spasm of smooth muscles (intestine) Delay of peristalsis, GIemptying (anti-dysentery)

Behavioral effects: analgesia, sedation, euphoriaClinical use: analgesia, cough, diarrheaSide effects: tolerance, dependence, withdrawal symptoms, addiction

Treatment of opiate addiction-heroin



-meperedine (Demerol): synthetic analgesic 1939, oral use 15min onset, 2-4hr duration

-methadone (Dolophin): synthetic analgesic 1945, oral use 15-30 min onset,4-6 hr duration with reduced euphoria

-hydropmorphone (Dilaudid), propoxyphene (Darvon), pentazocine (Talwin)

-hydrocodone (Vicodin)-oxycodone (oxycontin)-naloxone (narcan): antagonist

HallucinogensHallucinations: non-object bound sensory phenomena

-inclue misperceptions, misidentification, illusions, distortions, etc.Classifications of hallucinogens:

-by type of actions-by chemical relationship-by action: a) toxic metabolic effects (antibiotics, ACTH, aspirin, alcohol,

glue, paint, metalsb) delirium (atropine, PCP)c) psychogenesis (LSD, mescaline)

-by chemistry:a) acedtylcholine: cholinergicsb) dopamine: catecholaminesc) serotonin: indoleamines

Cholinergic hallucinogens:-family: solanacea (consolation) e.g. potato-genera: atropa, hyocymus, mandragora, datura

Species: Atropa Belladonna = deadly nightshade; Hyocymus Niger = henbane

(S&H); Mandragora Officinarum = mandrake [erotic dementia]; DaturaStramonnium = jimsonweedEffective components:

-atropine = dl-hyocyamine-scopolamine = l-hyoscine-l-hyosciamine

Atropine:-isolated in 1831, rapidly absorbed, excreted 24 hrs. Muscarinic blocker,

blocks post-ganglionic parasympathetic NS. Dry mouth, increased HR, excitement,delirium, coma, loss of memoryPhysostigmine (ESERIN):

-calabar or ordeal bean of Nigeria-AChE inhibitor, used for myasthenia gravis, glaucoma-Related to Sarin, mustard gas, chemical weapons-Long term effects: restlessness, tremors, confusion, ataxia, convulsions,

sweating, salivation, circulatory collapseAmanita Muscaria: the fly agaric mushroom

-Its home, Scandinavia, Siberia, Pratt Falls NY



-Effective ingredients: ibotenic acid, muscarine, muscimol (GABAaantagonist)

-Recyclable hallucinogen, excreted unchanged, causes twitching, trembling,euphoria, unreal illusions, sleepCatechol Hallucinogens:

-Peyote = Lophophora Williamsi, used by Native American Church-effective ingredient: mescaline-mescaline isolated 1896, synthesized 1919, readily absorbed, max. brain 30-

120 mine., half life 6 hours, duration 10-12 hours, 3mg/kg euphoria, 5mg/kghallucinations, LD50=370 mg/kg in rats, excreted unchangedMescaline effects: increased HR and BP, hyperthermia, pupil dilation, nausea,convulsions, tolerance, cross tolerance with LSD, chlorpromazine terminates badtripIndole hallucinogens:

-sources are extremely varied-Teonanacatl = psilocybe

Mexicana = magic mushroom in the land of MAZATECAThe magic Mushroom:

-effective ingredients: psilocybin (isolated by Hofmann 1958); psilocin 11/2times more potent and is a metabolite)

-Cross tolerance with LSD and mescalineBufo Alvarius (Sonoran Desert Toad)

-The venom contains bufotoxin, including 5-methoxy DMT and bufoteninAnagenanthera Peregrina = cohoba tree found in the Orinoco valley

-Virola elongate-Yanomano Indians

Effective ingredient : DMT (dimethyltryptamine), bufotenin

-DMT is poorly absorbed orally, inhaled or injected results in spectacularhallucinations BUSINESS MAN’S LUNCH Ayahuasca brew

Banisteriopsis caapi contains it (jungle vine)Harmala alkaloids to inhibit MAOPsychotria viridis leaves

-Effective ingredient: DMT and bufoteninOloliuqui = seeds of morning glory plant

-effective ingredient: lysergic acid amide (Hofmann)LSD

Albert Hofmann 1906-2008

“LSD: My Problem Child” Sandoz Laboratoriesd-lysergic acid (SAURE) diethylamideSynthesized by Hofmann 1938His first trip 1943, LSD is distributed for research 1950Lysergic acid is derived from the ergot fungusErgotism: St. Anthony’s fire



LSD is most potent hallucinogen known-0.05mg 10-12 hr trip-24 hrs completely excreted-max liver, min brain-visual system, Limbic system RF

Mechanism of Action:-serotonin hypothesis: occupies receptors temporarily-inhibits 5HT release, and turnover of SE is down

Pharmacological properties-sympathomimetic, vasoconstriction, pupil dilation, hyperthermia, HR and

BP up, tachycardia (rapid heartbeat), alertness-facilitates RF co-laterals, Thorazine blocks the effect, tolerance develops in

3-4 days but lasts only a week

Behavioral effects:-personality and social context dependent-euphoria, confusion, perceptual, and cognitive distortions-spirals then vivid visual hallucinations

Side effects:-no lethal dose known, no dependence-possible panic attack, especially in people with behavior disorders-flashback (less than 1:1000) in normal vs. psychiatric population (3:1000)-no chromosomal breakage, no teratogenic effects (malformation in babies)-effects superimposed on symptoms

MarijuanaMary Jane, reefer, tea, pot, grass, weedHemp plant leaves, from the resin comes hashishUnusual Plant: no nitrogenEffective ingredient: THC (tetrahydrocannibanol)

Raphael Mechoulam isolated itHistory

2737 B.C. Chinese Medical Compendium1000 A.D. north AfricaThe Old Man of the Mountain, Al-Hassan

1830 France; the Hashishan Club1870 British Royal Comission Report1926 The New Orleans Report1944 The LaGuardia Report: delta-9-THC

FateWhen smoked, absorption in 5 minWhen swallowed, absorption 30-60minMetabolite: 11 hydroxy THC detectable 8 days after a single dose



Slow clearance results in additive effects (reversed tolerance)Highly lipophilic

Mechanism of ActionAllyn Howlett (1988)Cannabinoid receptors CB1

-Endocannabinoids:Anandamide2-arachidonoyl glycerol (2-AG)

-Neuromodulation-Receptors on presynaptic GABA terminals-Increase SE and DA-reduce ACh (possible memory effects?)

Behavioral effects:-Animals: sedation, reduced aggression, hypothermia, reduced food

intake, trance-like state, analgesia, behavioral tolerance, impaired timing-Mice without CB1 remain fearful forever

(implication for PTSD)-Human: increase PR, HR, appetite, red eye, dry mouth, dizziness,

vomiting (alcohol) [if you’re a pussy], enhanced sensory experience, confidence,

hilarity, hallucinations, mood change, flashback, bronchitis, lower testosterone,amotivational syndrome

-Reduces pain

No lethal dose known in humansLD50: 1270 mg/kg (male rats) and 730mg/kg (female rats)

administered orally dissolved in sesame oilMedical benefits: cancer and AIDS by increasing appetite and decreasing

nauseaHerpes simplex viruses, glaucoma, multiple sclerosisTolerance and dependence develop from daily intense use

-Chills, headache, tension, etc.Currently no treatment existsHerbal cannabinoids: spice, mojo, K2Synthetics: JWH-018 and CP 47,497

-high affinity to receptors

Shaffer Commission Report

"drugs and behavior" syracuse university lecture notes

Documents