Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Abstract

Introduction- Women are more vulnerable to cocaine’s reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine. Here we asked if sex chromosome complement (SCC) influences vulnerability to cocaine use. Methods- We used the four core genotype (FCG) mouse that produces gonadal males and females with either XX or XY SCC. Mice were gonadectomized and implanted with either an estradiol (E2) or cholesterol-filled pellet. This allowed us to determine effects of SCC in the absence (cholesterol treated) and presence of tonic high physiological hormone levels (estradiol). Acquisition of cocaine self-administration was determined over a 12-day period using an escalated dose procedure (0.3 mg/kg/infusion, sessions 1-6; 0.6 mg/kg/infusion, sessions 6-12). Results- Without estradiol treatment, a greater percentage of castrated XY mice acquired cocaine self-administration and did so at a faster rate than XX castrates and ovariectomized XY females. These same XY males acquired sooner, infused more cocaine, and directed more nose pokes to the rewarded nose-poke hole than XX castrates and XY males receiving E2. Conclusion- Our results suggest that in gonadal male mice, SCC and estradiol can modulate the reinforcing effects of cocaine which may influence the likelihood of cocaine use.

Role of Hormones in Substance Use Disorders

“…Finally, Le et al [18] use a genetic model that has been employed to study sex differences for over 20 years [19], the four core genotype (FCG) mouse. This model is used to test the hypothesis that genes on X-and/or Y-chromosomes are involved in sexually dimorphic responses to cocaine.…”

“…There are several candidate genes, on the X-chromosome, that escape X-inactivation and their message and protein are present in higher amounts in females than in males. Le et al [18] are currently working to determine which of these genes are critical for sex differences in addictive behaviors.…”