Sex Differences in Anxiety During Cocaine Withdrawal
Drug abuse among women is a major societal health problem that has been under-investigated until recently (http://www.nida.nih.gov). Current advances show statistically significant differences between males and females in all phases of drug exposure (acquisition, steady-state maintenance, escalation, dysregulation, withdrawal, relapse, and treatment). Clinical evidence demonstrates that females are more susceptible to relapse compared to males and that this relapse is accompanied by a negative emotional state, notably anxiety. Physiological fluctuations (e.g. menstrual cycle), during drug exposure and following drug abstinence, may contribute to increased female sensitivity to the anxiogenic effects of cocaine. In female rats, gonadal hormones modulate dopamine activity in the nucleus accumbens (NAcb) providing support for sex differences in cocaine’s mechanisms of action. The δ-opioid receptor (DOR) undergoes desensitization following chronic cocaine administration in male rats through a D1R dependent mechanism. This desensitization may mediate anxiogenic responses induced by chronic cocaine administration in females. The guiding hypothesis is that female hormones, via actions on dopamine and opioid systems, may contribute to the increase in anxiety exhibited during cocaine withdrawal.
The co-expression of DOR and D1R is evident in a subset of neurons in the NAcb and striatum. This co-existence provides a cellular substrate for the regulation of DOR function by D1R activation. In basal conditions, D1R activation activates Gs which causes an increase in adenylyl cyclase (AC) activity, while activation of DOR activates Gi which inhibits AC activity. Interestingly, cocaine attenuates the ability of DOR to inhibit AC activity possibly through a D1R dependent mechanism. The inhibition of AC’s causes a lack of inhibition on cAMP production providing a functional measure of DOR desensitization.
The elevated-plus maze will be used to examine anxiety-like behaviors in female rats during abstinence from chronic cocaine administration. These behaviors will be correlated to the estrous cycle my monitoring hormonal fluctuations using vaginal lavage and analysis of blood estrogen levels. The contribution of DOR in cocaine-induced anxiety during withdrawal will also be determined by examining DOR desensitization using adenylyl cyclase and trafficking of DOR using electron microscopy.