Transcript DRUG A - University of Kentucky

Gender Differences in
Alcohol and Drug Response
Thomas H. Kelly, PhD
Department of Behavioral Science
College of Medicine
University of Kentucky
(859) 323-5206
[email protected]
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
Estrogen Modulation of Dopamine
Neurotransmission
Becker, 2000
Amphetamine Effects
Across the Menstrual
Cycle
Justice & de Wit, 1999
Amphetamine
Effects Across
the Menstrual
Cycle: A
Replication
White, Justice & de Wit, 2002
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
R
Light
ON
L
R
Light
OFF
L
R+ (e.g., Food)
S
No Consequence
No Consequence
R+ (e.g., Food)
S
Drugs Exert Stimulus
Control
R
R+ (e.g., Food)
S
Drug
L
R
No Consequence
No Consequence
Placebo
L
R+ (e.g., Food)
S
Methods
Training Phase
Two DRUG A Sampling Sessions
Control Phase
Up to 12 Sessions to correctly identify
DRUG A vs. NOT DRUG A
Correct = $$$
Test Phase
Test various doses of training drug during different
menstrual cycle phases.
Test phase only during particular menstrual cycle
phase(s) with hormone pretreatment.
Drug-discrimination task
Drug A
60
Not Drug A
0
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, Drug
Discrimination and cardiovascular measures.
placebo
15 mg/70 kg d-amphetamine
% Drug-Appropriate Responding
% Drug-Appropriate Responding
d-Amphetamine Discrimination
100
80
60
40
100
80
60
40
20
20
0
0
30
60
90
120
Time (min)
150
180
PL
3.125
7.5
15
d-amphetamine (mg/70 kg)
d-amphetamine
d-amphetamine + estradiol
100
% Drug-Appropriate Responding
% Drug-Appropriate Responding
% Drug-Appropriate Responding
d-Amphetamine Discrimination:
Estradiol Pretreatment
80
60
40
20
0
PL
3.125
7.5
15
d-amphetamine (mg/70 kg)
d-amphetamine
d-amphetamine + estradiol
100
% Drug-Appropriate Responding
% Drug-Appropriate Responding
% Drug-Appropriate Responding
d-Amphetamine Discrimination:
Estradiol Pretreatment
3.125 mg/70 kg d-amphetamine
80
60
40
20
0
30
60
90
120
Time (min)
150
180
Subject Ratings Like Drug
Subject Ratings Like Drug
VAS: Like Drug
Subject Ratings Like Drug
Subject Ratings Like Drug
ARS: Stimulated
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
Biosynthesis of Neurosteroids
Allopregnanolone
Pisu & Serra, 2004
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 (?)
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
Progesterone Modulation of Triazolam
Effects in Postmenopausal Women
McAuley et al., 1995
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
Grant et al., 1997
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