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Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugs Henry Lester

neurotransmitter transport inhibitors. enzyme inhibitors. Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugs Henry Lester. This material is scattered throughout Kandel; see Nestler et al. http://site.ebrary.com/lib/caltech/docDetail.action?docID=10251590. Disclaimer

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Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugs Henry Lester

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  1. neurotransmitter transport inhibitors enzyme inhibitors Bi / CNS 150 Lecture 13 Monday, October 28, 2013 Recreational drugs Henry Lester This material is scattered throughout Kandel; see Nestler et al http://site.ebrary.com/lib/caltech/docDetail.action?docID=10251590

  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. Coca Harvest in Bolivia, ca. 1950

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

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

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

  8. From Previous Lectures Na+-coupled cell membrane neurotransmitter transporters: major targets for drugs of therapy and abuse 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 Trademarks: Presynaptic terminals Na+-coupled cell membrane dopamine transporter Na+-coupled cell membrane serotonin transporter cytosol outside

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

  10. Knockout mice in pharmacology (Behavioral observations) 1. The m-opioid receptor m-opioid receptor KOs specifically lack responses to certain types of pain (next slide). 2. The a4b2 nicotinic receptor a4 or b2 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. --------------------------------------------------- 5. But NMDA receptor knockouts die at birth: an uninformative result

  11. Two behavioral tests often used on knockout mice Pain: Mice are placed on a hotplate at 55o 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: http://www.olar.caltech.edu/iacuc-sops.htm Self-administration of a drug

  12. “poppy that brings sleep” (opium) marijuana, hemp tobacco coca yeast grain fungus; Salem witch trials? Caporael, Science, 1976 Jean Nicot, French ambassador to Portugal coffee tea based on plant ergot

  13. Gordon A. Alles noted the properties of Ephedra vulgaris, used against asthma. He synthesized amphetamine (Benzedrine). Caltech BS, 1922; MS, 1924; PhD, 1926. Research Associate in Biology, 1939-1963

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

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

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

  17. Routes into the body

  18. Most recreational drugs act at < 10-5 M. Ethanol is an exception

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

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

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

  22. Recreational drugs have varying overall effects

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

  24. “Journal Club”: fMRI measurements on a hallucinogenic 5-HT2A agonist in human brain 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. Left hemisphere midline Right hemisphere % cerebral blood flow change relative to pre-infusion Decreased cerebral blood flow after psilocybin v. after placebo Time (min) Carhart-Harris et al, PNAS 2012

  25. 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.

  26. 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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