Neuropharmacology: Stimulants

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Lecture 18 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on the pharmacokinetics, pharmadynamics, and epidemiology.

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Neuropharmacology: Stimulants

  1. 1. StimulantsBrian J. Piper, Ph.D.
  2. 2. Goals• Examples – Methamphetamine – Cocaine – Khat• Pharmacodynamics• Pharmacokinetics• Epidemiology• Overdose
  3. 3. Amphetamines _ _Amphetamine Methamphetamine
  4. 4. History of Amphetamine• 1887: first synthesized by L. Edeleano• 1932: SKF introduces Benzedrine• 1970s: peak use in the U.S.
  5. 5. She may be tired for either of two reasons:*because she is physically overworked. If thisis the case, you prescribe rest because rest isthe only cure for this kind of physical tiredness*because she is mentally “done in”. Many ofyour patients---particularly housewives---arecrushed under a load of dull, routine dutiesthat leave them in a state of mental andemotional fatigue. For these patients, you mayFind “Dexedrine” an ideal prescription.“Dexedrine” will give them a feeling of energyand well being, renewing their interest in lifeand living.
  6. 6. Amphetamine Sensitization• Rats given 2.0 mg/kg of d-amphetamine once per day for 10 days• Measure amount of drug-induced rotational behavior each day
  7. 7. Pharmacodynamics• Mechanisms – VMAT reversal – DAT reversal – DAT reuptake inhibition
  8. 8. Microdialysis for Dopamine (DA) 1. 2 0.75 mg/infusion 700 0.50 mg/infusion 1. 0.25 mg/infusion 0 600 0.00 mg/infusion 0. 8 500Increase 0. 400 6in DA 300 0. 4 200 AMPH 0. 2 100 0 0 80 160 240 –40 0 40 80 120 160 200 Time (min) Time (min)
  9. 9. 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
  10. 10. 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 (Faces of Methamphetamine)
  11. 11. 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:http://www.methproject.org/ads/tv/tracy.htmlhttp://www.montanameth.org/View_Ads/index.php
  12. 12. True of 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
  13. 13. True or False: “the MMP results in Montana 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
  14. 14. Other Faces ofMethamphetamine
  15. 15. Other Faces of Methamphetamine Andre AgassiRobert Downey, Jr. Ted Arthur HaggardStacy Ann Ferguson “Fergie”
  16. 16. Methamphetamine Epidemiology (MtF) % Reporting “fairly easy” or “very easy” to get.Past year use of crystal. Year Year
  17. 17. Meth & Young-Adults
  18. 18. Meth & 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
  19. 19. Flyers Posted at:* OHSU* Coffee shops, Book stor* Grocery stores* Drug Tx programs•Needle exchange program•Crystal Meth AnonymousExclusion Criteria:* born before 35 weeks gestational age* epilepsy* Tourette’s syndrome* cerebral palsy* congenital abnormalities* severe brain trauma* Fetal Alcohol Syndrome* uncorrected visual impairments
  20. 20. Meth/Polysubstance Use Unexposed (N=35) Exposed (N=31)Trimesters of Methamphetamine 0 (0) 2.5 (0.3)***Income while pregnant : <15,000 17.1% 76.2*Income currently : >35,000 51.4% 60.0%Maternal Age at Birth (years) 26.9 (1.1) 29.8 (1.5)Nicotine 17.1% 76.2***Alcohol 11.4% 71.4%***Marijuana 11.4% 58.8%*Biological father involved 85.7% 44.8%***Number of other children 2.7 (0.3) 1.3 (0.3)**In home Piper et al. (2011) Pharm Biochem Behav
  21. 21. Reduced Academic Performance in Exposed Children Unexposed (N=35) Exposed (N=31) Birth Weight (g) 3,279 (114) 3,367 (194) Females 42.9% 53.3% Ethnicity (% non-Caucasian) 25.7% 20.0% Age at testing (7-9) 8.4 (0.2) 8.1 (0.2) Below Grade Level (%) 3.0% 25.9%* Below Reading Level (%) 20.6% 38.5%Piper et al. (2011) Pharm Biochem Behav .
  22. 22. Memory Island Visible (x Hidden (x 4) 4)Rizk-Jackson et al. (2006) Behav Brain Res 2006;173(2):181-90, Piper et al. Behav Brain Res.
  23. 23. Memory Island
  24. 24. Memory Island Performance is Reduced by Exposure
  25. 25. Increased Rates of ADHD .
  26. 26. Behavioral Rating Inventory of Executive Function (BRIEF)• Please rate whether the following behaviors are never, sometimes, or often a problem (1-3 points): – Emotional Control (EC) : overreacts to small problems – Inhibit (INH): interrupts others – Shift (SHI): becomes upset with new situations – Working Memory (WM): when given three things to do, remembers only the first or last – Initiate (INI): has trouble coming up with ideas for what to do in play time – Plan/Organize (PO): gets caught up in details and misses the big picture – Organization of Materials (OM): cannot find things in room – Monitor (MON): does not check work for mistakes – Behavioral Regulation Index + Metacognition Index = Global Executive Composite (Mean= 50.0, SD = 10)Gioia GA, Isquith PK, Guy SC, et al. (2000). Behavioral Rating Inventory of Executive Function: Professional Manual. Psychological Assessment Resources: Lutz.
  27. 27. “Clinically Significant” Behavioral Problems in Exposed Children*** p < .0005, ** p < .005, * p< .05 Piper et. al. (in review) Psychopharmacology .
  28. 28. Selectivity of Domains Altered Unexposed ExposedIQ (WASI) 104.5 (3.7) 95.1 (3.5)# Vocabulary 51.0 (2.2) 46.3 (1.7) # Matrix Reasoning 53.8 (1.9) 48.4 (2.2) # Block Design 52.7 (2.2) 50.0 (1.8)Spatial Span (Forward) 5.7 (0.3) 5.3 (0.3)Spatial Span (Backward) 4.9 (0.4) 4.5 (0.4)Family Pictures (Immediate) 57.0 (5.3) 46.5 (5.1)Family Pictures (Delayed) 52.6 (5.7) 43.4 (5.1)# p < .10 Piper et al. (2011) Pharm Biochem Behav
  29. 29. Blood levels of “Ice”Blood level(ng/ml) Hours
  30. 30. Spiders • Web building was Before After examined the day before and after Vehicle stimulant administration. Araneus diadematus 0.04 uL/mg Methamphetamine 0.10 uL/mg CaffeineHesselberg & Vollrath (2004) Physiology & Behavior, 82, 519-529.
  31. 31. History of Cocaine• 1850s: Cocaine isolated from Erythroxylon coca 1856-1939• 1880s: Sigmund Freud evolves from strong cocaine proponent (therapy for heroin addiction, antidepressant) to become more cautious & stops using (migraines) in 1896• 1904: Cocaine is removed as an ingredient from Coca Cola
  32. 32. History of Cocaine• 1984: Crack emerges in LA, NY, & Miami• 1985: Sentencing laws, 500 g cocaine or 5 g crack = 5 years, 100:1!• 2010: Fair Sentencing Act (Kucinich & Paul): 18:1 Keith Haring, 1958-1990http://www.youtube.com/watch?v=ytJpZguSy2U
  33. 33. Pharmacodynamics• Reuptake inhibition of – DAT – NET – SERTShort video of Cocaine and Neurotransmission:http://www.utexas.edu/research/asrec/cocaine.mov
  34. 34. Is cocaine addictive?• Cocaine withdrawal: – does not produce physical symptoms – does produce psychological symptoms: • exhaustion • depressed mood • anhedonia • anxiety • craving
  35. 35. Other Neurotransmitters?Immunostraining for DAT (A) or tyrsoineHydroxylase (B) in wild-type (+/+), hetero-Zygotous or DAT knock-out (-/-) mice. Sora et al. (2001). PNAS, 95, 7699-7704.
  36. 36. Other Neurotransmitters?Rocha et al. (1998) Nature Neuroscience, 1, 132-137.
  37. 37. Other Neurotransmitters (5-HT/NE)? • Autoradiography using [123I]RTI55 & also with a SERT inhibitor (Alaproclate)Rocha et al. (1998) Nature Neuroscience, 1, 132-137.
  38. 38. Conditioned Place Preference • CPP to cocaine is present in DAT or SERT knock-outs • Double knock-outs do not show CPPSora et al. (2001). PNAS, 98, 5300-5305.
  39. 39. DAWN ER VisitsRank Me: Stimulants, MJ, Heroin, Cocaine
  40. 40. DAWN ER Visits
  41. 41. Comparison Cocaine Methamphetamine Schedule II (surgery) II (ADHD) Base form “crack” “crystal” Half-life (hours) 1 11 Metabolite Benzoylecgonine (BE) amphetamine Mechanism(s) DA, NE, 5-HT uptake inhibition DA, NE, 5-HT uptake inhibition + releaseJulien (2009) Primer of drug action.
  42. 42. Methylphenidate• Treatment for ADD/ADHD• Blocks dopamine reuptake, increases norepinephrine• Pills crushed and snorted O CH C O CH 3 N Methylphenidate
  43. 43. MtF: “Amphetamines” = Adderall & Ritalin
  44. 44. Juvenile Methylphenidate alters CPP to cocaineRats received methylphenidate (2 mg/kg) or saline as juveniles (PD 20-35) followed bycocaine in adulthood (PD 60). Juvenile methylphenidate altered the conditioned placepreference (A) and locomotor (B) responses to cocaine.Anderson et al. (2001) Nature Neuroscience, 5,13-14.
  45. 45. Cathinone– active agent in Khat (or qat)– chewed– synthetic version (meth- cathinone) O C CH NH 2 CH 3 Cathinone
  46. 46. PET images from control subjects, Parkinson’s patients, and abstinent methamphetamine and methcathinone users (average period of abstinence, 3 years). WIN-35,429 binding to the dopamine transporter. Neurotoxicity?McCann et al. (1998). J Neurosci 18, 8417-8422.
  47. 47. Sympathomimetic Summary • Pharmacokinetics • Pharmacodynamics: DA, NE, 5-HT • EpidemiologyNora Volkow “Mechanisms Underlying Use and Abuse of Stimulant Drugs”http://videocast.nih.gov/summary.asp?Live=1997
  48. 48. DA : dopamine, MAO: Monoamine oxidase
  49. 49. Methylphenidate = Ritalin
  50. 50. Top row: radioactive cocaine labelingBottom row: radioactive methylphenidate labelingBasal Ganglia: brain area important for movement
  51. 51. Time course for cocaine (2, 4, 8, 10, 20, 30, & 40) orMethylphenidate (2, 4, 8, 10, 20, 30, 40, 60, 90) minutes
  52. 52. High is shown in green
  53. 53. DA: dopamine; MAO A: monoamine oxidase, type A
  54. 54. Outliers: extreme scores statistically
  55. 55. Raclopride: drug that binds to D2 receptors
  56. 56. Top: DAT Occupancy by dose (mg/kg)Bottom: self-rated high by dose (mg/kg)
  57. 57. DA: dopamine receptor, autoreceptor: presynaptic
  58. 58. po: per os or by mouth (oral administration)
  59. 59. DA: dopamine, DAT: dopamine transporter, MP: methylphenidate
  60. 60. Microdialysis for DA (dopamine) following stress, methylphenidate,or stress + methylphenidate
  61. 61. Effects of MP on Perception of the Task andCorrelations with MP-induced DA changes
  62. 62. Effects of Methylphenidate (MP) when given with a Mathematical or a Neutral Task on[11C]raclopride binding, coditions: Placebo + Neutral task; MP + neutral task, Placebo +Mathematical Task, Methylphenidate + Mathematical task
  63. 63. Gr: tyros6.2 (cheese) amino acid Treatment for Parkinson’s disease Neurotransmitter important for movement, reinforcement Neurotransmitter important for cognition
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