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![Page 1: Gender Differences in Alcohol and Drug Response Thomas H. Kelly, PhD Department of Behavioral Science College of Medicine University of Kentucky (859)](https://reader030.fdocuments.net/reader030/viewer/2022032606/56649e925503460f94b97bec/html5/thumbnails/1.jpg)
Gender Differences in Alcohol and Drug Response
Thomas H. Kelly, PhD
Department of Behavioral Science
College of Medicine
University of Kentucky
(859) 323-5206
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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– SSRI’s 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 behavior…
Hormones do not “cause” behavior; they alter probabilities of responses to given stimuli
One 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
• Alzheimer’s/Dimentia• Parkinson’s 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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Becker, 2000
Estrogen Modulation of Dopamine Neurotransmission
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Justice & de Wit, 1999
Amphetamine Effects Across the Menstrual
Cycle
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White, Justice & de Wit, 2002
Amphetamine Effects Across the Menstrual
Cycle: A Replication
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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
No Consequence
SR+
LightOFF
R
L (e.g., Food)
No Consequence
SR+
LightON
R
L
(e.g., Food)
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Drugs Exert Stimulus Control
No Consequence
SR+
Placebo
R
L (e.g., Food)
No Consequence
SR+
Drug
R
L
(e.g., Food)
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Methods
Training Phase
Control Phase
Test Phase
Two DRUG A Sampling Sessions
Up to 12 Sessions to correctly identify DRUG A vs. NOT DRUG A
Correct = $$$
Test various doses of training drug during different menstrual cycle phases.
Test phase only during particular menstrual cycle phase(s) with hormone pretreatment.
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Drug A Not Drug A
60 0
Drug-discrimination task
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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
• 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
Assessment: ARS, VAS, ARCI, DSST, DrugDiscrimination and cardiovascular measures.
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d-Amphetamine Discrimination
0
20
40
60
80
100
placebo
15 mg/70 kg d-amphetamine
% D
rug
-Ap
pro
pri
ate
Res
po
nd
ing
Time (min)
30 60 90 180150120
0
20
40
60
80
100
% D
rug
-Ap
pro
pri
ate
Res
po
nd
ing
d-amphetamine (mg/70 kg)
PL 3.125 7.5 15
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d-Amphetamine Discrimination:Estradiol Pretreatment
% D
rug
-Ap
pro
pri
ate
Res
po
nd
ing
% D
rug
-Ap
pro
pri
ate
Res
po
nd
ing
0
20
40
60
80
100
d-amphetamine (mg/70 kg)
PL 3.125 7.5 15
d-amphetamine
d-amphetamine + estradiol
% D
rug-
App
ropr
iate
Res
pond
ing
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d-Amphetamine Discrimination:Estradiol Pretreatment
% D
rug
-Ap
pro
pri
ate
Res
po
nd
ing
% D
rug
-Ap
pro
pri
ate
Res
po
nd
ing
d-amphetamine
d-amphetamine + estradiol
% D
rug-
App
ropr
iate
Res
pond
ing
0
20
40
60
80
100
30 60 90 180150120
3.125 mg/70 kg d-amphetamine
Time (min)
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VAS: Like Drug
d-amphetamined-amphetamine + estradiol010203040506070803060901801501203.125 mg/70 kg d-amphetamine0010203040506070803060901801501200 mg/70 kg d-amphetamine0010203040506070803060901801501207.5 mg/70 kg d-amphetamine00102030405060708030609018015012015 mg/70 kg d-amphetamine0Time (min)
Su
bje
ct R
atin
gs
Lik
e D
rug
Su
bje
ct R
atin
gs
Lik
e D
rug
d-amphetamine
d-amphetamine + estradiol
0
10
20
30
40
50
60
70
80
30 60 90 180150120
3.125 mg/70 kg d-amphetamine
0
0
10
20
30
40
50
60
70
80
30 60 90 180150120
0 mg/70 kg d-amphetamine
0
0
10
20
30
40
50
60
70
80
30 60 90 180150120
7.5 mg/70 kg d-amphetamine
0
0
10
20
30
40
50
60
70
80
30 60 90 180150120
15 mg/70 kg d-amphetamine
0
Time (min)
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ARS: Stimulated
Su
bje
ct R
atin
gs
Lik
e D
rug
Su
bje
ct R
atin
gs
Lik
e D
rug
d-amphetamine
d-amphetamine + estradiol
Time (min)
6
8
10
12
14
16
30 60 90 180150120
0 mg/70 kg d-amphetamine
0
6
8
10
12
14
16
30 60 90 180150120
3.125 mg/70 kg d-amphetamine
0
6
8
10
12
14
16
30 60 90 180150120
15 mg/70 kg d-amphetamine
0
6
8
10
12
14
16
30 60 90 180150120
7.5 mg/70 kgd-amphetamine
0
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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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Pisu & Serra, 2004
Biosynthesis of Neurosteroids
Allopregnanolone
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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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• 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
Progesterone Modulation of Triazolam Effects in Postmenopausal Women
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McAuley et al., 1995
Progesterone Modulation of Triazolam Effects in Postmenopausal Women
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Grant et al., 1997
Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle
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Grant et al., 1997
Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle
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Grant et al., 1997
Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle
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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 behavior…
These hormones do not “cause” behavior; they can modulate behavior via both genomic and nongenomic neuropharmacological mechanisms
Estrogens and progestins can affect many complex behaviors
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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
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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