Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration.

Recent evidence demonstrates that there are sex differences in behavioral responses to cocaine. Further, reproductive gonadal hormones (estrogen, progesterone and testosterone) have been further implicated in mediating some of the cocaine-induced alterations. To better understand sex differences and the role of gonadal hormones in cocaine-induced locomotor and stereotypic behavior, intact and gonadectomized male and female Fischer rats were randomly assigned to either chronic cocaine (15 mg/kg) or saline treatments for 14 days followed by a challenge administration (7 days after the last cocaine/saline administration). Locomotor (ambulatory and rearing) and stereotypic activities were measured on days 1, 7 and 14 as well as after withdrawal/challenge with cocaine. Overall, intact female rats consistently showed a rapid (acquired by day 7) and longer lasting (persistent through the challenge dose) sensitization for all locomotor behaviors than any of the other groups. In contrast, intact males developed sensitization of these locomotor activities only in response to chronic cocaine administration, and after withdrawal and drug challenge the sensitization to cocaine-induced locomotor activity was no longer present. In female rats, gonadectomy affected ambulatory activity but not total and rearing responses after acute, sub-acute, chronic and challenge response to cocaine. On the other hand, castrated male rats were affected in cocaine-induced ambulatory activity but not rearing activity. In intact male rats, cocaine-induced stereotypic activity was rapidly and persistently sensitized after 7 days of cocaine administration, where gonadectomized male rats developed sensitization to cocaine-induced stereotypic activity only after a challenge cocaine administration. Although cocaine induced stereotypic activity, no statistically significant differences were observed between intact and ovariectomized female rats or throughout the different lengths of cocaine administration. After a challenge of cocaine, corticosterone levels were induced in all experimental groups. Moreover, no differences in levels of benzoylecgonine, a cocaine metabolite, were observed. Similar to our previous observations after acute cocaine administration, after challenge of cocaine, an increase in progesterone and a decrease in testosterone levels were observed in intact females and males, respectively. In summary, endogenous hormones seem to be involved in the behavioral activation and development of sensitization to cocaine.

Effects of cocaine on c-fos and preprodynorphin mRNA levels in intact and ovariectomized Fischer rats.

Psychostimulants such as cocaine have been shown to regulate c-fos and opioid gene expression in male rats. However, little information is available on cocaine effects in female rats or how the ovarian hormones, estrogen and progesterone, modulate these effects. In this study we used quantitative solution hybridization assays to measure c-fos and preprodynorphin (PDYN) mRNA levels after cocaine administration in the caudate/putamen of intact male and female rats or ovariectomized (OVX) female rats that were pretreated with vehicle, estrogen and/or progesterone. The c-fos mRNA levels were increased in intact male and female rats after 30min or 3h of one single cocaine injection and after 14 days of single daily cocaine injections. The c-fos mRNA levels were also increased after 30min of a single cocaine injection in OVX female rats that were treated with vehicle, estrogen and/or progesterone. The PDYN mRNA levels did not change after 30min, 3h or 14 days in intact male or female rats. However, PDYN mRNA levels were increased in the caudate/putamen of OVX female rats pretreated with vehicle or a combination of estrogen and progesterone but not in OVX female rats that were pretreated with either estrogen or progesterone alone. Our data suggest hormonal regulation of cocaine effects on PDYN mRNA levels which may modulate cocaine-induced behaviors in female rats.