The effects of ovarian hormones on responses to cocaine in Sprague Dawley rats.

Cocaine use is a growing public health concern, and may be disproportionately problematic for women because the pattern of cocaine abuse is more severe for women than men. Moreover, individual differences such as sex and hormonal status exert profound influences on responses to cocaine. The purpose of this thesis is to characterize the effects of ovarian hormones on two preclinical measures of addiction: behavioral sensitization to cocaine and acquisition of cocaine self-administration behavior. Behavioral sensitization is associated with increased responsiveness to psychomotor stimulants and is thought to reflect the underlying neurobiology involved in craving. The first three studies investigated estradiol's effect on behavioral sensitization to 3 doses of cocaine. There were no sex differences or effects of hormones at 25 mg/kg cocaine, likely because animals quickly reached a ceiling effect at such a high dose of cocaine. At 10 mg/kg cocaine, estradiol administration enhanced sensitized behaviors during the testing period. At 5 mg/kg cocaine, estradiol enhanced induction of behavioral sensitization during the testing period and after a period of abstinence from estradiol administration. Overall, females treated with estradiol had significantly more cocaine-stimulated behaviors than did all other groups. It is concluded that estradiol's modulation of cocaine-induced behaviors differs dependent upon the dose of cocaine. Further, estradiol enhancement persists even in the absence of continued estradiol administration. Previous estradiol administration also potentiates amphetamine-stimulated dopamine (DA) release from striatal tissue in vitro, long after discontinuation of estradiol administration. Females pretreated with estradiol and sensitized to cocaine had greater DA release than females pretreated with estradiol and saline, and females pretreated with oil vehicle and sensitized to cocaine. The fourth study evaluated the effect of estradiol pretreatment on acquisition of cocaine self-administration behavior. Drug self-administration is a self-evident animal correlate of drug-taking behavior. Ovariectomized females that were pretreated with estradiol for 3 weeks did not show enhanced acquisition of cocaine self-administration behavior. However, ovariectomized females that received estradiol benzoate 30 minutes before testing acquired self-administration more quickly than other groups. This suggests that prior hormonal status alone does not account for enhanced responses to cocaine. Furthermore, castrated males that received exogenous estradiol administration did not have enhanced acquisition and were not significantly different from other male groups. Although this is the first study to investigate effects of estradiol on acquisition of cocaine self-administration in castrated males, these results support the theory that effects of estradiol are sexually dimorphic, enhancing responses to cocaine only in females. Sex differences in response to exogenous estradiol administration are likely due to sex differences in the influence of circulating gonadal hormones on the brain. In females but not males, circulating estradiol may act on brain systems that mediate drug reward and modulate drug-taking behavior. The fifth study examined whether concurrent progesterone and estradiol administration would affect acquisition of self-administration behavior. At the dose employed in the study, progesterone suppressed estradiol-enhanced acquisition of cocaine self-administration. Females treated with estradiol and progesterone attained fewer infusions of cocaine, took longer to acquire cocaine self-administration and ingested less cocaine than females treated with estradiol alone. Taken together, these data demonstrate that estradiol exerts a powerful influence on preclinical indices of addiction, enhancing behavioral and neurochemical responses to cocaine in gonadectomized females, but not males. Furthermore, progesterone may be a viable tool to reduce vulnerability to drug seeking behavior in females.PhDBiological SciencesHealth and Environmental SciencesNeurosciencesPharmacologyPhysiological psychologyPsychobiologyPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124084/2/3121952.pd