Gender Differences in Alcohol and Drug Response Thomas H. Kelly, PhD Department of Behavioral...

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

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

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


0

10

20

30

40

50

60

70

80

30 60 90 180150120


0

0

10

20

30

40

50

60

70

80

30 60 90 180150120


0

0

10

20

30

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60

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30 60 90 180150120


0

0

10

20

30

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50

60

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80

30 60 90 180150120


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


Time (min)

6

8

10

12

14

16

30 60 90 180150120


0

6

8

10

12

14

16

30 60 90 180150120


0

6

8

10

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14

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30 60 90 180150120


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

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

Gender Differences in Alcohol and Drug Response Thomas H. Kelly, PhD Department of Behavioral...

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