The effects of gonadal hormones on the development and expression of the stimulant effects of morphine in male and female rats.

Previous studies have shown that the behavioral activating effects of the stimulant drug amphetamine are augmented in female rats by estradiol. Here we studied the effects of gonadectomy and gonadal hormone replacement on the stimulant effects of morphine in both females and males. Groups of intact, ovariectomized (Ovex), and Ovex females given estradiol benzoate (EB) (5 micrograms), and groups of intact, castrated, and castrated males given testosterone propionate (30 micrograms) were administered five injections of morphine sulphate (10 mg/kg, i.p.) or saline at 3-day intervals. Activity was monitored on each occasion for 2 h. Among females treated with morphine, intact and Ovex-EB animals showed progressive enhancement of activity over sessions, whereas Ovex animals showed no change. Three days after the last pre-exposure session, all animals received 5 mg/kg morphine in a test for sensitization. In spite of the lower levels of activity in Ovex animals, animals from all groups previously exposed to morphine showed a sensitized response to morphine compared with those receiving morphine for the first time. These findings are virtually identical to our previous findings in female rats treated with amphetamine. Among males, only intact animals showed a progressive increase in morphine-induced activity and only in the second hour of testing, but, overall, there was no significant effect of either group or drug during the pre-exposure phase. On the test for sensitization, as seen in females, those males that had been exposed to morphine previously showed a sensitized responses to morphine. There were, however, no differences in activity levels between the groups of males. We conclude that although gonadal hormones, and in particular estradiol, may modify the magnitude of the response to amphetamine and morphine, they appear not to be involved in those neurochemical and neuronal changes that occur during and following repeated drug exposures, and that underlie the enhanced sensitivity to the stimulant effects of a drug seen when such animals are compared with animals receiving the drug for the first time.