Temporal effects of estrogen and progesterone on behavioral and endocrinological responses to acute cocaine administration.

Estrogen and progesterone have been postulated to play a key role modulating cocaine-induced behavioral and neurochemical activation in female rats. This study investigated the temporal relationship between estrogen and progesterone in the modulation of cocaine-induced behavioral alterations. Ovariectomized Fischer rats received s.c. injections of estradiol benzoate 48 hr prior to cocaine or saline treatment and one s.c. injection of progesterone concurrently or 1, 4, 20, 24, 30, 44 or 48 hr after estrogen treatment. Forty-eight hours after estrogen treatment rats received either a single i.p. injection of 15 mg/kg of cocaine or 0.9% saline. Overall, cocaine induced increases in locomotor behaviors (ambulatory and rearing activity). A bimodal interaction between estrogen and progesterone was observed in the modulation of all locomotor activities. A gradual increase in behaviors, which peaked when progesterone was administered 24 hr after estrogen was followed by an inhibition of both ambulatory and rearing activity when progesterone was administered for a shorter period of time. This estrogen and progesterone interaction was not observed in the modulation of cocaine-induced stereotypic activity. However, shorter administration of progesterone in relation to estrogen administration resulted in lowered benzoylecgonine plasma levels when compared to longer progesterone administration times. On the other hand, longer administration of progesterone (48 hr of estrogen and progesterone) caused increases in corticosterone levels in cocaine-treated rats. Thus, the temporal interaction between estrogen and progesterone in the regulation of cocaine metabolism and hypothalamic-pituitary-axis (HPA) activation do not completely correlate with that observed for locomotor behavioral activation. Taken together, these results suggest that temporal interactions between estrogen and progesterone may underlie some of the previously reported estrous cycle and sex effects on cocaine-induced behavioral and endocrinological alteration.