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Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugsHenry Lester This material is scattered throughout Kandel; see Nestler et al enzyme.

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Presentation on theme: "Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugsHenry Lester This material is scattered throughout Kandel; see Nestler et al enzyme."— Presentation transcript:

1 Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugsHenry Lester This material is scattered throughout Kandel; see Nestler et al enzyme inhibitors neurotransmitter transport inhibitors

2 2 Disclaimer 1.Do not alter your pattern of prescription drug compliance as a result of this course. 2.Consult a medical professional for further guidance about prescription drugs. H. A. L. is not aware of all trends in current medical practice, is not a physician, and cannot prescribe.

3 Week 3: Recreational drugs  Addictive drugs  Abused drugs  Illegal drugs

4 4 Coca Harvest in Bolivia, ca. 1950

5 5 cocaine in the test tube cocaine base: directly extracted from the plant with organic solvents treatment with acid (HCl) cocaine hydrochloride: a salt, readily soluble treatment with base: ammonia or Na bicarbonate, then heat to drive off HCl

6 6 H+H+ blood, CSF lungs, nose, stomach H+H+ cocaine base (crack) cocaine in the body cocaine hydrochloride South American Indians use Ca(OH) 2 from limestone to shift this equilibrium Lipid barrier, e. g. membrane(s)

7 neurotransmitter transporters ligand-activated channels GPCRs G protein-activated channels N C LSD morphine-heroin tetrahydrocannabinol amphetamine cocaine ketamine nicotine ?alcohol? caffeine* (*= intracellular target) enzymes Targets for Recreational Drugs 

8 8 Na + -coupled cell membrane neurotransmitter transporters: Antidepressants (“SSRIs” = serotonin-selective reuptake inhibitors): Prozac, Zoloft, Paxil, Celexa, Luvox Drugs of abuse: MDMA Attention-deficit disorder medications: Ritalin, Dexedrine, Adderall Drugs of abuse: cocaine amphetamine Na + -coupled cell membrane serotonin transporter Na + -coupled cell membrane dopamine transporter cytosol outside major targets for drugs of therapy and abuse Presynaptic terminals From Previous Lectures Trademarks:

9 Endogenous ligand morphine-heroinagonistendorphins (peptides) THCagonistanandamide nicotineagonistacetylcholine cocaineantagonistdopamine amphetamine & derivatives antagonist, false substrate noradrenaline, serotonin, dopamine ethanolagonist?G protein? LSDagonistserotonin caffeineinhibitorcyclic AMP (intracellular) ketamineantagonistglutamate

10 Primary Target ClassDetails morphine-heroin GPCR (G protein-coupled receptor) (Gi)  -opioid receptor THCGPCR (Gi)cannabinoid receptor nicotineagonist-activated channel  4  2 nicotinic acetylcholine receptor cocaine plasma membrane neurotransmitter transporter dopamine transporter amphetamine & derivatives vesicular & plasma membrane neurotransmitter transporter vesicular monoamine transporter (VMAT) ethanol? K channel ? G protein-gated inward rectifier GIRK1/2 LSDGPCR (Gq)serotonin 5-HT2a receptor caffeineenzyme cyclic AMP phosphodiesterase ketamineligand-activated channelNMDA glutamate receptor

11 11 Knockout mice and one application for them Gene (DNA) Hypothesis: the response to a drug requires your favorite molecule Interrupt the gene with a detectable protein (knock out the gene) EGFP Replace the mouse gene with the altered gene Select the mouse with the altered gene Breed many identical mice measure drug response vs

12 12 Knockout mice in pharmacology (Behavioral observations) 1. The  -opioid receptor  -opioid receptor KOs specifically lack responses to certain types of pain (next slide). 2. The  4  2 nicotinic receptor  4 or  2 nicotinic receptor knockouts: (1) respond less to nicotine in pain tests (next slide) (2) fail to self-administer nicotine (next slide). 3. The dopamine transporter Dopamine transporter knockout mice: (1) are hyperactive, (2) show less response to cocaine, (3) self-administer cocaine less 4. Cannabinoid receptors Cannabinoid receptor knockouts have little overt differences to normal mice. They don’t show these effects of THC and anandamide: (1) decreased pain responses and (2) decreased heart rate But NMDA receptor knockouts die at birth: an uninformative result

13 13 Two behavioral tests often used on knockout mice Pain: Mice are placed on a hotplate at 55 o C. The experimenter notes the time to lick paws, jump, etc. The experiment terminates at 30 s, regardless of the outcome. A pain-relieving drug increases the time to react No permanent harm to the mouse... Carefully regulated: Self-administration of a drug

14 Source (species: ) morphine-heroin Papaver somniferum tetrahydrocannabinol Cannabis sativa, C. indica nicotine Nicotiana tabacum cocaine Erythroxylum coca amphetamine synthetic ethanol Saccharomyces cerevisiae (fermentation) LSD synthetic caffeine Coffea sp., Camellia sinensis ketaminesynthetic “poppy that brings sleep” (opium) marijuana, hemp tobacco coca coffee tea yeast ergot grain fungus; Salem witch trials? Caporael, Science, 1976 based on plant Jean Nicot, French ambassador to Portugal

15 15 Gordon A. Alles noted the properties of Ephedra vulgaris, used against asthma. He synthesized amphetamine (Benzedrine). Caltech BS, 1922; MS, 1924; PhD, Research Associate in Biology,

16 proton-coupled vesicular serotonin transporter cytosol ATP-driven proton pump SERT MDMA serotonin vesicle MDMA MDMA-H + H+H+ MDMA dissipates the vesicle’s H + store, preventing the vesicle from pumping serotonin serotonin depleted serotonin vesicle MDMA-H + MDMA is a “false substrate” for two transporters 3,4-methylenedioxy-N-methamphetamine (MDMA, “ecstasy”, “XTC”, “molly”) pK a ~ 8.5 Rudnick & Wall, PNAS 1992 MDMA or Amphetamines Release Transmitter into the External Medium

17 17 A modified patch clamp circuit and pipette allow us to detect dopamine electrochemically by oxidizing the adjacent hydroxyl groups of dopamine cytosol synaptic cleft carbon fiber A

18 18 In dopamine transporter knockout mice (“DAT -/-”), presynaptic stimuli (“^”) lead to longer individual dopamine release pulses; but amphetamine fails to release dopamine Amphetamine Jones et al J Neurosci 18, p 1979

19 Eat / drinkInhaleSmokeInject morphine-heroin tetrahydrocannabinol nicotinechew cocaine amphetamine & derivatives ethanol LSD caffeine ketamine Routes into the body

20 20 Active Concentration morphine-heroin ~ 1  M tetrahydrocannabinol ~ 1  M nicotine ~ 1  M cocaine ~ 1  M amphetamine ~ 1  M ethanol> 1 mM LSD~ 10 nM caffeine ~ 10  M phencyclidine ~ 1  M Most recreational drugs act at < M. Ethanol is an exception

21 21 Nestler Figure 6-1 Dopaminergic Neurons: “pleasure / reward / well-being” system highlighted. Several recreational drugs affect this system

22 22 Only a few thousand neurons in the brain make noradrenaline Nestler Figure 6-7

23 System-level Action Dopamine “Pleasure” system Noradrenaline “Readiness” system “Perception- Association” system “Decreased neuronal activity” morphine-heroin tetrahydrocannabinol nicotine cocaine amphetamine ethanol ? LSD caffeine ketamine

24 24 Serotonergic neurons project to many higher brain regions, and also descend to spinal cord raphe nuclei simplified from Nestler Figure 6-10

25 Overall Action morphine-heroininhibitory tetrahydrocannabinolinhibitory nicotineexcitatory cocaineexcitatory amphetamine & derivatives excitatory ethanolinhibitory LSDhallucinations caffeineexcitatory ketamine hallucinations, antidepressant Recreational drugs have varying overall effects

26 First, subjects’ Reports: fMRI measurements on a hallucinogenic 5-HT2A agonist in human brain Carhart-Harris et al, PNAS 2012 psilocybin → psilocin from mushrooms:

27 “Journal Club”: fMRI measurements on a hallucinogenic 5-HT2A agonist in human brain Decreased cerebral blood flow after psilocybin v. after placebo Left hemisphere midline Right hemisphere % cerebral blood flow change relative to pre-infusion Time (min) Most active regions before psilocybin become least active during the drug! Authors suggest that psilocin activates some GABA neurons, decreasing overall activity of the more numerous glutamatergic neurons. Carhart-Harris et al, PNAS 2012

28 Recreational usePrescription use* Non-prescription (“over the counter”) use morphine-heroinIllegal Schedule II pain control Weaker analogs: cough & diarrhea tetrahydrocannabinol 28.5 g, (CO, WA); > 21; taxed 20 states incl. CA; taxed nicotine Taxed; no sales to minors Smoking cessation: gum, lozenge, patch, inhaler cocaineIllegal ear, nose & throat surgery amphetamine & derivatives Illegal Schedule II ADD / ADHD; narcolepsy Diet pills ethanol Taxed; no sales to minors Rare, detox (methanol or ethylene glycol) LSDIllegal caffeineLegal In some migraine medications With antihistamines ketamineIllegalSchedule III Legal status of Recreational Drugs in the USA, late 2013 *Pharmaceutical companies may promote only "on label" use. Physicians may prescribe according to the standard of care, which may be "off label" use.

29 29 What changes occur in the brain during chronic exposure to an addictive drug? Today’s lecture is only the first step in such studies. End of Lecture 13


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