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Gender Differences in Alcohol and Drug Response

Gender Differences in Alcohol and Drug Response. Thomas H. Kelly, PhD Department of Behavioral Science College of Medicine University of Kentucky (859) 323-5206 thkelly@uky.edu. Pharmacokinetics. Bioavailability Absorption and first-pass metabolism Distribution

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Gender Differences in Alcohol and Drug Response

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  1. Gender Differences in Alcohol and Drug Response Thomas H. Kelly, PhD Department of Behavioral Science College of Medicine University of Kentucky (859) 323-5206 thkelly@uky.edu

  2. Pharmacokinetics • Bioavailability • Absorption and first-pass metabolism • Distribution • Body fat/volume of distribution • Protein binding • Body size • Metabolism • Phase I CYP450 superfamily • Phase II reactions • Excretion • Glomular filtration rate varies with body weight

  3. Pharmacodynamics • CNS drugs • Striatal dopamine release and reuptake • SSRI’s and other antidepressants • Anit-anxiety medications • Anesthetics • Seizure medications • Drug Abuse • Cardiovascular drugs • Energy drugs • Immune system drugs

  4. Neuropharmacology of Estrogen and Progesterone

  5. Hormones have powerful influences on behavior…Hormones do not “cause” behavior; they alter probabilities of responses to given stimuliOne hormone can have many effects: A single hormone can affect complex behaviors Pfaff, Phillips & Rubin, 2004

  6. Neuropharmacology of Estrogens and Progestins • Function as neurotransmitters acting at nuclear receptor sites to regulate gene activity in the neuron • Function as direct or indirect neuromodulators of neuronal membrane receptor systems that are targeted by classical neurotransmitters (e.g., dopamine, 5-HT, GABA, glutamate, etc.)

  7. Estrogens • Steroid hormones (~ 30) produced by the ovaries • Estradiol • Estrone • Estriol • Synthesized in the CNS from circulating testosterone

  8. Behavioral Effects of Estrogens • Sexual Behavior • Learning & Memory • Mood • Neural Structure/Organization • Alzheimer’s/Dimentia • Parkinson’s Disease • Drug Abuse • Depression • Brain Injury • Pain

  9. Estrogens • Nuclear Receptor • ER • ER • Neurotransmitter Modulation • Acetylcholine • Dopamine • Norepinephrine • Serotonin • Glutamate • GABA • Opioid

  10. Estrogen Modulation of Dopamine • Increases DA synthesis • Upregulation of DA receptors • Reduced DA clearance • Enhanced DA release

  11. Estrogen Modulation of Dopamine Neurotransmission Becker, 2000

  12. Amphetamine Effects Across the Menstrual Cycle Justice & de Wit, 1999

  13. Amphetamine Effects Across the Menstrual Cycle: A Replication White, Justice & de Wit, 2002

  14. Drug Discrimination • Drug cues established via discrimination training appear to be mediated by drug actions at the cellular level • In vivo behavioral model of receptor function

  15. R R + + R R S S Stimulus Control (e.g., Food) Light ON L No Consequence No Consequence Light OFF L (e.g., Food)

  16. R R + + R R S S Drugs Exert Stimulus Control (e.g., Food) Drug L No Consequence No Consequence Placebo L (e.g., Food)

  17. Methods Training Phase Two DRUG A Sampling Sessions Up to 12 Sessions to correctly identify DRUG A vs. NOT DRUG A Correct = $$$ Control Phase Test various doses of training drug during different menstrual cycle phases. Test phase only during particular menstrual cycle phase(s) with hormone pretreatment. Test Phase

  18. Drug-discrimination task Drug A Not Drug A 60 0

  19. 10 Subjects • Healthy adult females who were all using oral birth control including a 5-6 day placebo phase • Occasional stimulant use • All provided written consent prior to participation and were paid for participation • Study was approved by the UK Medical IRB

  20. 9:00 Check In 9:10 Assessment 9:15 Snack 9:45 Dose 10:15 Assessment 10:45 Assessment 11:15 Assessment 11:45 Assessment 12:15 Assessment 12:45 Assessment Daily Schedule Assessment: ARS, VAS, ARCI, DSST, Drug Discrimination and cardiovascular measures.

  21. d-Amphetamine Discrimination

  22. d-Amphetamine Discrimination:Estradiol Pretreatment % Drug-Appropriate Responding % Drug-Appropriate Responding

  23. d-Amphetamine Discrimination:Estradiol Pretreatment % Drug-Appropriate Responding % Drug-Appropriate Responding

  24. VAS: Like Drug Subject Ratings Like Drug Subject Ratings Like Drug

  25. ARS: Stimulated Subject Ratings Like Drug Subject Ratings Like Drug

  26. Estrogen modulates the neuropharmacological and behavioral effects of d-amphetamine • Extracellular dopamine increased • Stereotypical behaviors enhanced • Self-report of stimulant drug effects enhanced • Self-report effects are not easily replicated • Discriminative stimulus effects enhanced

  27. Progestins • Steroid hormones produced by the ovaries, placenta and adrenals • Progesterone • Progesterone Metabolites • Progestins are also synthesized in the CNS

  28. Biosynthesis of Neurosteroids Allopregnanolone Pisu & Serra, 2004

  29. Behavioral Effects of Progestins • Sexual Behavior • Learning & Memory • Mood • Epilepsy • Depression • Sleep • Anxiety • Stress • Alcohol/Drug Abuse • Brain Injury

  30. Progestins • Nuclear Receptor • PRA • PRB • Neurotransmitter Modulation • GABAA Receptors • Nicotinic Acetylcholine Receptors • Sigma • NMDA

  31. Progesterone Regulation of GABA • Upregulate GABA receptors • Modulate GABA binding (?) • Direct Agonist (?)

  32. Progesterone Modulation of Triazolam Effects in Postmenopausal Women • 16 healthy postmenopausal women not using HRT • Random Assignment • Placebo + Triazolam (0.5 mg IV) • Progesterone (300 mg PO) + Triazolam (0.5 mg IV) • Lower doses administered to progesterone group • Behavioral effects adjusted to triazolam levels

  33. Progesterone Modulation of Triazolam Effects in Postmenopausal Women McAuley et al., 1995

  34. Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle Grant et al., 1997

  35. Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle Grant et al., 1997

  36. Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle Grant et al., 1997

  37. Progesterone Modulates the Behavioral Effects of GABA Agonists • Progesterone enhances the performance impairment engendered by Triazolam • Enhanced discriminative stimulus effects of GABAA agonists • Alcohol • Triazolam • Allopregnanolone

  38. Estrogens and progestins can have powerful influences on behavior…These hormones do not “cause” behavior; they can modulate behavior via both genomic and nongenomic neuropharmacological mechanismsEstrogens and progestins can affect many complex behaviors

  39. Adverse Consequences: Alcohol • Men vs. Women • Women consistently achieve higher BAL’s for drinking the same amount as men • Due to body water? • Due to differential enzyme activity? • Other factors • Women progress to alcoholism more rapidly • Effects of estrogen and progesterone • Cycling of women’s hormones

  40. Gender Differences: Alcohol • Pharmacology • Differential activity of alcohol dehydrogenase in men and women • Women have a lower proportion of body water • Women have a lower first pass metabolism • Combined, these factors allow women to achieve consistently higher BALs even when drinking the same amount as men

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