Sex Differences in Drug Abuse:
Lessons from Preclinical Studies
Jill B. Becker
University of Michigan
Molecular and Behavioral Neuroscience Institute Psychology Department Psychiatry Department Neuroscience Program Reproductive Sciences Program
What do we mean by Sex Differences?
Sex Differences in the Brain are Structural
Sex Differences in the Brain are also Functional: Research of Doreen Kimura
How do Males and Females Become Different?
• Biological Development: Genetic Sex
determines gonadal sex -> then gonadal hormones influence brain development.
• Hormones Released are Different Between Males and Females. • Hormone-Environment Interactions:
Sex differences in effects of Hormones and Hormone Responses to Environment during development and in the adult.
POSSIBLE CAUSES OF SEX DIFFERENCES IN BRAIN & BEHAVIOR
Males and females exhibit sex differences because they secrete different hormones. Males and females exhibit sex differences because the same hormones are acting on a sexually dimorphic brain. Males and females exhibit sex differences because they secrete different hormones and the hormones are acting on a sexually dimorphic brain.
How do you study sex differences in brain and behavior?
Is there a sex difference?
Yes
No
Consider possibility of sex-specific forces that cancel each other (De Vries 2004)
Yes publish
Test for role of sex hormones at time of testing
No
Test for permanent differentiating effects of gonadal steroids
No
Yes
publish
Test sex-specific cell-autonomous effects of sex chromosome genes
No
Yes publish
Consider possibility that experimental conditions used for tests were different from intial test: Did you lose the sex difference along the way?
Becker et al (2005) Endocrinology
Sex Differences in Drug Abuse
•Time from first exposure to onset of chronic use is shorter in females than in males •Females present for treatment consuming more cocaine than males •Path to addiction may be sexually dimorphic Is there a biological basis for this sex difference?
Women and Drug Abuse
* 9 million women have used illegal drugs in the past year in the USA (40% of drug addicts are women) • 3.7 million women have taken prescription drugs non-medically during the past year. * Among cocaine users 12-17 years old
51.5% are women, in the 18-25 age group 42.0% are women, for cocaine users 26 years and older 38.8% are women (SAMHSA, 2005).
Do female rats acquire cocaine self-administration more rapidly and at lower doses than males?
Sex Differences in Cocaine Self-Administration
Hu, Crombag, Robinson, & Becker 2004 Neuropsychopharmacology
Sex differences in Total intake at All doses of Cocaine
Hu, Crombag, Robinson, & Becker 2004 Neuropsychopharmacology
Estradiol enhances acquisition of cocaine self-administration in females. Females take more cocaine than males. Estradiol does NOT enhance cocaine self-administration in male rats.
Estradiol enhances the Motivation to take cocaine in female rats
SENSITIZATON
• Repeated administration of cocaine results in a progressive enhancement of the behavioral response to these drugs. • Associated with addictive behaviors and/or craving.
Sex differences (CAST vs OVX) Estradiol pre-treatment -> Behavioral Sensitization to Cocaine
1400 1200 125
Net Rotation / Hr
1000 800 600
OVX + E
Rate of Sensitization
**
100
***
* OVX
CAST
75
50
400 SHAM 200 0
0 1 2 3 4 5 6 7 8 9 10 11 12
25
0 SHAM CAST OVX OVX+E
Sessions (20 mg/kg Cocaine)
Treatme nt
Hu and Becker, 2003 J Neurosci
What factors influence an individual’s response to drugs of abuse?
Sex/Gender and Ovarian Hormones of the Individual Prior Stress History of the Individual
Individual Differences in Impulsivity/Risk Taking Behaviors
Maternal Stress during late gestation
1. Dam receives restraint stress during final week of the rat’s 3 week gestational period. 2. Offspring are tested as young adults.
Maternal Stress During Late Gestation Increases the Behavioral Sensitization to Cocaine in Female Offspring.
Locomotor Behavior Induced by Cocaine
1600 PS Male Coc 1600
* +
1400
1400
PS Female Coc NPS Female Coc
NPS Male Coc
1200 1200
1000 Distance (m) Distance (m)
1000
*
800
800
600
600
400
400
200
200
0 Day 1 Day 12
0 Day 1 Day 12
Maternal Stress During Gestation enhances cocaine self-administration of male offspring
Mark B. Thomas
100 100
80 % of Individuals Acquired
80
% of Individuals Acquired
60
60
PS Male
40 NPS Male
PS Female 40 NPS Female
20
20
0 1 3 5 7 Session 9 11 13 15
0
1
3
5
7
Session
9
11
13
15
Acquisition of cocaine self-administration
striatum
ASCENDING DOPAMINE NEURONS
& SN
Activation of Ascending Dopamine Neurons Occurs
In Vivo Microdialysis to monitor dopamine in brain
Extracellular Dopamine Concentrations in Striatum are lower in Ovariectomized Females and Females During Diestrus than in Males or Females on Estrus
XIAO & BECKER, 1994
DOPAMINE TERMINAL
Estradiol rapidly enhances the cocaine-induced increase in dopamine in brains from females but not males
In vivo microdialysis
RESULTS OF DIALYSIS AND in vitro EXPERIMENTS:
There are sex differences in basal dopamine concentrations in the striatum and in striatal dopamine receptors. In females: stimulated dopamine release is altered by ovarian hormones.
Removal of gonadal hormones attenuates and Estradiol treatment reinstates the dopamine response in females, there is no efect of gonadal hormones in males. Estradiol priming can enhance the effect of acute estradiol in females. Estradiol acts directly on the striatum to enhance DA release in females.
Model for the Mechanism Mediating the Effect of mERa In Striatum and NAcc.
Increased expression of ERa in striatum through gene transfer enhances the effect of estradiol to attenuate GABA release
Schultz et al, submitted
THE ACTION OF ESTRADIOL TO ENHANCE DOPAMINE RELEASE MEDIATES SOME OF THE EFFECTS OF ESTRADIOL IN FEMALES AND MAY CONTRIBUTE TO SEX DIFFERENCES IN DRUG ABUSE. • FEMALES ARE MORE SUSCEPTIBLE FOR DRUG ABUSE: INDEPENDENT OF GONADAL HORMONES - so sexual differentiation of the brain during development contributes to sex differences in drug abuse liability. • ESTRADIOL IN FEMALES INCREASES VULNERABILITY TO ADDICTION BY ENHANCING THE MOTIVATION TO TAKE COCAINE.
CONCLUSIONS
• WORKING HYPOTHESIS: The greater increase in dopamine induced by drugs of abuse in females results in more robust ‘down-stream’ changes in the brain, and greater liability for addiction.
AN IMPROVED UNDERSTANDING OF SEX/GENDER DIFFERENCES IN THE BRAIN IS IMPORTANT FOR YOUR HEALTH
Sex/Gender appropriate diagnoses and treatments: Neurological Disorders Psychiatric Disorders Neuro-Immune system disorders Drug Abuse Pain Management
Collaborators
Li Xiao Terry Bazzett William J. Jenkins Lisa R. Jackson Ming Hu Charles Rudick Brooke Davis Elizabeth Peckham Jennifer Cummings Hongyan Yang Mark B. Thomas Wei Zhao Kristin Schultz Terry E. Robinson Hans Crombag D. James Surmeier Paul G. Mermelstein Robert T. Kennedy Christopher Watson Huda Akil Stanley J. Watson
This Research was Supported by:
NIDA
NATIONAL INSTITUTE ON DRUG ABUSE
Office of Research On Women’s Health