Post on 30-Dec-2015
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– 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
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
Neuropharmacology of Estrogen and Progesterone
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
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.)
Estrogens
• Steroid hormones (~ 30) produced by the ovaries– Estradiol– Estrone– Estriol
• Synthesized in the CNS from circulating testosterone
Behavioral Effects of Estrogens
• Sexual Behavior• Learning & Memory• Mood• Neural Structure/Organization
• Alzheimer’s/Dimentia• Parkinson’s Disease• Drug Abuse• Depression• Brain Injury• Pain
Estrogens
• Nuclear Receptor– ER– ER
• Neurotransmitter Modulation– Acetylcholine– Dopamine– Norepinephrine– Serotonin– Glutamate– GABA– Opioid
Estrogen Modulation of Dopamine
• Increases DA synthesis
• Upregulation of DA receptors
• Reduced DA clearance
• Enhanced DA release
Becker, 2000
Estrogen Modulation of Dopamine Neurotransmission
Justice & de Wit, 1999
Amphetamine Effects Across the Menstrual
Cycle
White, Justice & de Wit, 2002
Amphetamine Effects Across the Menstrual
Cycle: A Replication
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
Stimulus Control
No Consequence
SR+
LightOFF
R
L (e.g., Food)
No Consequence
SR+
LightON
R
L
(e.g., Food)
Drugs Exert Stimulus Control
No Consequence
SR+
Placebo
R
L (e.g., Food)
No Consequence
SR+
Drug
R
L
(e.g., Food)
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.
Drug A Not Drug A
60 0
Drug-discrimination task
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
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.
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
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
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)
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)
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
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
Progestins
• Steroid hormones produced by the ovaries, placenta and adrenals– Progesterone– Progesterone Metabolites
• Progestins are also synthesized in the CNS
Pisu & Serra, 2004
Biosynthesis of Neurosteroids
Allopregnanolone
Behavioral Effects of Progestins
• Sexual Behavior• Learning & Memory• Mood
• Epilepsy• Depression• Sleep• Anxiety• Stress• Alcohol/Drug Abuse• Brain Injury
Progestins
• Nuclear Receptor– PRA– PRB
• Neurotransmitter Modulation– GABAA Receptors
– Nicotinic Acetylcholine Receptors– Sigma
• NMDA
Progesterone Regulation of GABA
• Upregulate GABA receptors
• Modulate GABA binding (?)
• Direct Agonist (?)
• 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
McAuley et al., 1995
Progesterone Modulation of Triazolam Effects in Postmenopausal Women
Grant et al., 1997
Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle
Grant et al., 1997
Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle
Grant et al., 1997
Discriminative Stimulus Effects of Alcohol and Allopregnanolone Across the Menstrual Cycle
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
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
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
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