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Introductory Psychology: Neuropharmacology III


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lecture 9 from a college level introduction to psychology course taught Fall 2011 by Brian J. Piper, Ph.D. ( at Willamette University, includes substituted amphetamines (methamphetamine and MDMA), epidemiology, pharmacokinetics, pharmacodynamics

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Introductory Psychology: Neuropharmacology III

  1. 1. Drugs & Behavior III: Amphetamines Brian J. Piper, Ph.D.
  2. 2. Amphetamines _ _Amphetamine Methamphetamine
  3. 3. AmphetaminesAmphetamine Methamphetamine __ _ 3,4-methylenedioxymethamphetamine
  4. 4. History of Methamphetamine• 1893: Synthesized by Nagai Nagayoshi in Japan• 1940s- : Popular with military• 1960s- : used for short-term treatment of obesity, narcolepsy, and, later, ADHD• 1983- : federal and states laws attempt to reduce use by decreasing availability of ephedrine and pseudoephedrine• 2000s- : several aggressive advertising campaigns are aimed at reducing demand
  5. 5. Montana Meth Project • Businessman Thomas Siebel supported graphic advertising in 2005 • Goal was to reach each teenager 3+ times/week (TV, radio, print).To View Ads:
  6. 6. True of False: “the MMP results inMontana have been more significant than any other drug prevention program in history”? Youth Risk Behavior Survey • High School students were asked about lifetime methamphetamine use before and after the Montana Methamphetamine Project. Anderson (2010) J Health Econ
  7. 7. True or False: “the MMP results in Montanahave been more significant than any other drug prevention program in history”? Youth Risk Behavior Survey • High School students were asked about lifetime methamphetamine use before and after the Montana Methamphetamine Project. Anderson (2010) J Health Econ
  8. 8. Other Faces ofMethamphetamine
  9. 9. Other Faces of Methamphetamine Andre AgassiRobert Downey, Jr. Ted Arthur HaggardStacy Ann Ferguson “Fergie”
  10. 10. History of EcstasyEcstasy is 3,4-methylenedioxymethamphetamine (MDMA)• 1912: Synthesized by German pharmaceutical company Merck by Anton Kollisch (1888-1916)• 1950’s: U.S. Army conducted animals studies to determine the lethal dose.• 1970’s: Mental health workers advocated using MDMA with psychotherapy. There are ongoing studies to use MDMA with talk therapy for anxiety related to post-traumatic stress disorder and among terminally ill cancer patients.• 1985: Drug Enforcement Agency (DEA) classifies MDMA as Schedule I• 1990’s- today: MDMA is popular recreational drug, especially among young- adults.
  11. 11. Short-term effects of Ecstasy• Psychological • Physiological – Empathy – Increase in heart rate – Increased energy – Increase in blood pressure – Openness – Reduced appetite – Increased sensitivity to – Bruxism: grinding teeth sounds & touch – Trismus: jaw clenching
  12. 12. Example of tolerance • Rats received ecstasy (MDMA) on 6 days. Arrows indicate times of administration. • Panel A shows that MDMA altered core temperature on the 1st day. • Panel B shows that the same dose had less effects on the 3th day. • Panel C shows almost no effects by the 6th day.Piper et al. (2005) Developmental Psychobiology, 47, 145-157.
  13. 13. AmphetaminesAmphetamine Methamphetamine __ _ 3,4-methylenedioxymethamphetamine
  14. 14. Chemistry • Entactogen: touching within (Nichols) MDMA (methylenedioxymethamphetamine)MDA (methylenedioxyamphetamine) Amphetamine
  15. 15. Ecstasy = MDMA?
  16. 16. Drug Levels in the Blood: Individual Differences Following Oral Administration of MDMA Plasma MDMA for each marmoset that received 1 mg/kg. 80 70 60 M D M A (n g /m l)Ng/ml 50 Lexi 40 Eric Zale 30 Autumn 20 10 0 0 20 40 60 Time
  17. 17. Age Influences How YourBody Responds to Drugs Meyer, Piper,& Vancolli (2010) Annals of the New York Academy of Sciences.MDMA -----> MDA
  18. 18. Brain Chemistry• MDMA increases neurotransmitters (serotonin, norepinephrine, dopamine) & hormones (cortisol, prolactin)
  19. 19. Serotonin • Serotonin is 5-hydroxytryptamine (5-HT) • The brain uses the amino acid tryptophan (found in bananas, milk, yogurt) to make 5-HT. • 5-HT has been implicated in mood (anxiety, depression & aggression), appetite, sexuality, and cognition.See also:
  20. 20. Raphe nuclei• 5-HT cell bodies (somas) are found in the brainstem in the raphe nuclei.• 5-HT axons descend into spinal cord and ascend to the hippocampus and cortex.
  21. 21. Serotonin Transporter (SERT)• SERT is a protein found at the synapse and along the axon that removes 5-HT from the synaptic cleft.• SERT (shown in pink) brings 5-HT from the synaptic cleft back into the axon.• Serotonin reuptake inhibitors (e.g. Prozac or fluoxetine) prevent SERT from removing 5-HT.• The density of SERT is used as a index of the number of 5-HT axons and is altered by MDMA.
  22. 22. Long-term effects of High Dose MDMA on 5-HT neurons (animal data)• Weeks after MDMA treatment to animals, there is a reduction in 5-HT, 5-HT metabolites, and SERT which suggests a 5- HT axotomy (axons are cut).• Months to years after MDMA in monkeys, some brain areas still show a reduction in SERT and 5-HT (hypoinnervation). However, other areas show an abnormal increase in SERT and 5-HT (hyperinnervation).
  23. 23. Serotonin fibers in the caudate nucleus of a control squirrel monkey (A), a monkey that received 5 mg/kg MDMA 2 weeks (B), or 7 years (C) previously.Hatzidimitriou, G. et al. J. Neurosci. 1999;19:5096-5107
  24. 24. What about brain function?• Complex behaviors can be measured in non- human animals like: – Attention – Learning – Memory – “Emotion”
  25. 25. Object-Recognition Memory Task Rats were exposed to two identical objects in a 3-min sample phase. There was a retention delay (15 min), during which both objects were replaced: one replacement object was identical to the previous two, while the other was a novel object. Memory of the familiar object is indicated by the animal spending more time exploring the novel object during a 3-min choice phase.Figure from A. Ennaceur.
  26. 26. Adolescent MDMA decreases memory. Saline MDMA Sample (A) 25.6 (3.1) 23.5 (1.4) Test (A) 11.8 (2.0) 14.9 (1.4) Test (B) 24.7 (3.5) 20.0 (3.1) B/(A+B) 0.68 (0.03) 0.56 (0.04)*Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731
  27. 27. Adolescent MDMA reduces anxiety-like behavior. SALINE- MDMA- P VALUE BEHAVIOR TREATED TREATEDTotal arm entries 19.1 ± 3.0 27.4 ± 3.0 .074Open-arm entries 3.1 ± 1.4 7.9 ± 1.8 .058Open/Total (%) 12.8 ± 5.2 27.3 ± 5.3 .071Open-arm duration 41.4 ± 18.7 108.9 ± 20.3 <.05(sec)Closed-arm 507.4 ± 30.5 400.5 ± 30.3 <.05duration (sec)Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731.
  28. 28. Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731.
  29. 29. Spatial Memory In Rodents• Rodent research has found that early developmental Methamphetamine treatments cause persistent impairments in spatial memory.Acevedo SF, de Esch IJ, Raber J (2007) Neuropsychopharmacology 32:665-672
  30. 30. MDMA Summary• Short-Term Effects: – Empathy – hyperthermia, – ↑5-HT & Dopamine• Long-Term Effects: ↓5-HT
  31. 31. Amphetamine Comparison MDMA MethamphetamineHistory One-century One-centuryAcute Subjective Effects Empathy EuphoriaNeurotoxicity Serotonin DopamineSchedule I IIIAddiction No Yes
  32. 32. Hallucinogens Hallucinogens are psychedelic (mind-manifesting) drugs that distort perceptions andevoke sensory images in the absence of sensory Ronald K. Siegel input.
  33. 33. Hallucinogens LSD: (lysergic acid diethylamide) powerful hallucinogenic drug that is also known as acid. THC (delta-9-tetrahydrocannabinol): is the major active ingredient in marijuana (hemp plant) that triggers a variety of effects, including mild hallucinations. Hemp Plant
  34. 34. DrugsSummary