Mechanisms Mediating Sex Differences in the Effects of Cocaine.

Sex Differences;Cocaine Addiction;Estradiol;Dopamine;Cocaine Sensitization;Cocaine Self-administration;Physiology;Psychology;Science;Social Sciences;Psychology

Zhao, WeiRobinson, Terry E. ;

University of Michigan

关键词: Sex Differences;    Cocaine Addiction;    Estradiol;    Dopamine;    Cocaine Sensitization;    Cocaine Self-administration;    Physiology;    Psychology;    Science;    Social Sciences;    Psychology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/61686/zhaowei_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The patterns of cocaine use differ between men and women. Women are more likely and take shorter time to become cocaine dependent after initial use of cocaine. Behavioral sensitization is an animal model that allows us to explore plastic changes with repeated cocaine use and to understand factors influencing this process, which may be involved in addition. This dissertation is trying to further characterize cocaine sensitization in females and to examine the role of ascending midbrain dopaminergic system in sex differences in cocaine sensitization. This dissertation first reports that cocaine sensitization promotes the acquisition of cocaine self-administration in females, suggesting the reinforcing effect is enhanced as a result of sensitization in females as in males. In addition, cocaine sensitization is suggested to be associated with enhanced midbrain dopamine neuron reactivity in males, which has not yet been tested in nucleus accumbens in vitro. This dissertation for the first time show that enhanced stimulated dopamine release in vitro from nucleus accumbens as well as striatum after cocaine experience in females, suggesting the same hypothesis is applicable in females as in males. Furthermore, estradiol treatment enhances behavioral sensitization in females when it is given with repeated cocaine treatment as predicted. More importantly, by comparing the cocaine-induced behavioral activation post sensitization on challenge day with or without additional estradiol treatment, acute estradiol treatment is first found to enhance cocaine-induced behavioral activation on cocaine-sensitized rats, suggesting estradiol produces an independent activating effect on sensitized neural circuits to affect behavioral sensitization. Lastly, cocaine sensitization and associated changes of dopamine neuron reactivity in the striatum are first compared between males and females in one experiment. Repeated cocaine treatment results in sexually dimorphic patterns of both cocaine sensitization and cross-sensitization to amphetamine. Accordingly, neuroadaptive changes of amphetamine-induced dopamine efflux in the striatum associated with sensitization also exhibit a sexually dimorphic pattern. It suggests sex differences in behavioral sensitization might be associated with sex differences in DA neuron reactivity in the striatum. This work improves our understanding of gender differences in patterns of cocaine abuse and has important implications for the development of gender-specific therapies in cocaine addiction.