Women begin using cocaine, enter treatment at earlier ages than men, and have more severe cocaine use at intake than men. Thus, women progress from initial use to dependence faster than men do. This "telescoping" effect reflects a briefer time course for the development of medical consequences and behavioral/psychological factors characteristic of a dependence disorder. The studies proposed are a fundamentally important first step towards understanding structure-function relations in the induction and expression of drug-taking behavior and the long-term consequences of this behavior in both males and females. In this proposal we seek to identify the hormonal and developmental events that produce a sexually dimorphic ascending dopamine system that results in sex differences in drug abuse liability, and to identify some of the associated neural processes that mediate these sex differences. There are two times during development of the brain when hormones can influence its organization. In the rat these occur during the peri-natal period and again during the peri-pubertal period. Experiments are proposed to test the hypothesis that the enhanced vulnerability of females for cocaine abuse is dependent on the lack of exposure to gonadal hormones during the critical perinatal period, as well as subsequent exposure to ovarian hormones during the peripubertal period. Self-administration of cocaine will be used as the primary outcome measure. Acquisition of drug taking behavior during adolescence in humans is a strong predictor of drug abuse problems as an adult. We hypothesize that onset of hormone exposure during the peri-pubertal period contributes to increased vulnerability for the reinforcing and/or long-term consequences of cocaine treatment in both males and females. We will determine whether adolescence is a period of enhanced vulnerability for female vs. male rats to self-administer cocaine. Alternatively, it is possible that adolescents aren't more vulnerable to the addictive properties of the psychomotor stimulants, but that the long-term consequences of exposure to these drugs during adolescence result in increased susceptibility as an adult, this possibility will be examined as well. Finally, the neural basis of the organizational and developmental influences on sex differences in the response to cocaine will be examined by looking at dopamine in dialysate from striatum and nucleus accumbens. These experiments are a first step towards exploring the extent that sex differences in vulnerability for cocaine abuse impacts the striatum and nucleus accumbens.

Public Health Relevance

Women are more vulnerable to becoming addicted to cocaine than are men. The experiments proposed will investigate the neurodevelopmental processes that contribute to this gender difference in drug abuse using a preclinical model. The long-term goal of this project is to develop better intervention and treatment protocols for both men and women based on an improved understanding of neural basis of vulnerability to addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Cummings, Jennifer A; Jagannathan, Lakshmikripa; Jackson, Lisa R et al. (2014) Sex differences in the effects of estradiol in the nucleus accumbens and striatum on the response to cocaine: neurochemistry and behavior. Drug Alcohol Depend 135:22-8
Meitzen, John; Perry, Adam N; Westenbroek, Christel et al. (2013) Enhanced striatal *1-adrenergic receptor expression following hormone loss in adulthood is programmed by both early sexual differentiation and puberty: a study of humans and rats. Endocrinology 154:1820-31
Westenbroek, Christel; Perry, Adam N; Becker, Jill B (2013) Pair housing differentially affects motivation to self-administer cocaine in male and female rats. Behav Brain Res 252:68-71
Perry, Adam N; Westenbroek, Christel; Becker, Jill B (2013) Impact of pubertal and adult estradiol treatments on cocaine self-administration. Horm Behav 64:573-8
Cummings, Jennifer A; Clinton, Sarah M; Perry, Adam N et al. (2013) Male rats that differ in novelty exploration demonstrate distinct patterns of sexual behavior. Behav Neurosci 127:47-58
Cummings, Jennifer A; Becker, Jill B (2012) Quantitative assessment of female sexual motivation in the rat: Hormonal control of motivation. J Neurosci Methods 204:227-33
Zhao, Wei; Becker, Jill B (2010) Sensitization enhances acquisition of cocaine self-administration in female rats: estradiol further enhances cocaine intake after acquisition. Horm Behav 58:8-12
Becker, Jill B (2009) Sexual differentiation of motivation: a novel mechanism? Horm Behav 55:646-54
Schultz, Kristin N; von Esenwein, Silke A; Hu, Ming et al. (2009) Viral vector-mediated overexpression of estrogen receptor-alpha in striatum enhances the estradiol-induced motor activity in female rats and estradiol-modulated GABA release. J Neurosci 29:1897-903
Thomas, Mark B; Hu, Ming; Lee, Theresa M et al. (2009) Sex-specific susceptibility to cocaine in rats with a history of prenatal stress. Physiol Behav 97:270-7

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