Gender Differences in Alcohol and Drug Response

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Gender Differences in Alcohol and Drug Response

• Thomas H. Kelly, PhD
• Department of Behavioral Science
• College of Medicine
• University of Kentucky
• [phone]
• thkelly_at_uky.edu

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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

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Pharmacodynamics

• CNS drugs
• Striatal dopamine release and reuptake
• SSRIs and other antidepressants
• Anit-anxiety medications
• Anesthetics
• Seizure medications
• Drug Abuse
• Cardiovascular drugs
• Energy drugs
• Immune system drugs

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Neuropharmacology of Estrogen and Progesterone
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Hormones have powerful influences on
behaviorHormones 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

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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.)

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Estrogens

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

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Behavioral Effects of Estrogens

• Sexual Behavior
• Learning Memory
• Mood
• Neural Structure/Organization
• Alzheimers/Dimentia
• Parkinsons Disease
• Drug Abuse
• Depression
• Brain Injury
• Pain

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Estrogens

• Nuclear Receptor
• ER?
• ER?
• Neurotransmitter Modulation
• Acetylcholine
• Dopamine
• Norepinephrine
• Serotonin
• Glutamate
• GABA
• Opioid

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Estrogen Modulation of Dopamine

• Increases DA synthesis
• Upregulation of DA receptors
• Reduced DA clearance
• Enhanced DA release

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Estrogen Modulation of Dopamine Neurotransmission
Becker, 2000
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Amphetamine Effects Across the Menstrual Cycle
Justice de Wit, 1999
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Amphetamine Effects Across the Menstrual Cycle A
Replication
White, Justice de Wit, 2002
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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

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Stimulus Control
(e.g., Food)
Light
ON
L
No Consequence
No Consequence
Light
OFF
L
(e.g., Food)
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Drugs Exert Stimulus Control
(e.g., Food)
Drug
L
No Consequence
No Consequence
Placebo
L
(e.g., Food)
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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
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Drug-discrimination task
Drug A
Not Drug A
60
0
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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

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Daily Schedule

• 900 Check In
• 910 Assessment
• 915 Snack
• 945 Dose
• 1015 Assessment

• 1045 Assessment
• 1115 Assessment
• 1145 Assessment
• 1215 Assessment
• 1245 Assessment

Assessment ARS, VAS, ARCI, DSST,
Drug Discrimination and cardiovascular measures.
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d-Amphetamine Discrimination
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d-Amphetamine DiscriminationEstradiol
Pretreatment
Drug-Appropriate Responding
Drug-Appropriate Responding
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d-Amphetamine DiscriminationEstradiol
Pretreatment
Drug-Appropriate Responding
Drug-Appropriate Responding
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VAS Like Drug
Subject Ratings Like Drug
Subject Ratings Like Drug
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ARS Stimulated
Subject Ratings Like Drug
Subject Ratings Like Drug
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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

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Progestins

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

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Biosynthesis of Neurosteroids
Allopregnanolone
Pisu Serra, 2004
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Behavioral Effects of Progestins

• Sexual Behavior
• Learning Memory
• Mood
• Epilepsy
• Depression
• Sleep
• Anxiety
• Stress
• Alcohol/Drug Abuse
• Brain Injury

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Progestins

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

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Progesterone Regulation of GABA

• Upregulate GABA receptors
• Modulate GABA binding (?)
• Direct Agonist (?)

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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

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Progesterone Modulation of Triazolam Effects in
Postmenopausal Women
McAuley et al., 1995
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Discriminative Stimulus Effects of Alcohol and
Allopregnanolone Across the Menstrual Cycle
Grant et al., 1997
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Discriminative Stimulus Effects of Alcohol and
Allopregnanolone Across the Menstrual Cycle
Grant et al., 1997
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Discriminative Stimulus Effects of Alcohol and
Allopregnanolone Across the Menstrual Cycle
Grant et al., 1997
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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

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Estrogens and progestins can have powerful
influences on behaviorThese hormones do not
cause behavior they can modulate behavior via
both genomic and nongenomic neuropharmacological
mechanismsEstrogens and progestins can affect
many complex behaviors
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Adverse Consequences Alcohol

• Men vs. Women
• Women consistently achieve higher BALs 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 womens hormones

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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