Effect of gonadectomy on discriminative stimulus effects of morphine in female versus male rats.

Abstract

In a previous study, we found sex differences in the potency of morphine as a discriminative stimulus; the present study was designed to determine whether sex differences in gonadal hormones contribute to sex differences in morphine's discriminative effects. Adult female and male rats were gonadectomized (GNDZ) or sham-gonadectomized (SHAM), and then trained to discriminate 3.0 mg/kg morphine from saline. The ED50 for morphine discrimination was significantly lower in females than in males (0.66 +/- 0.12 vs. 1.25 +/- 0.16 mg/kg, respectively); ED50 values in GNDZ rats were slightly higher than in SHAM rats. The time course of morphine discrimination was not significantly different in females and males, whether GNDZ or not. The micro agonist fentanyl completely substituted for morphine in all rats, with no group differences in ED50 value. The micro agonists buprenorphine and nalbuphine substituted for morphine in nearly all females and in all SHAM males, but in only four of seven GNDZ males. The kappa agonist U69,593 did not substitute for morphine in rats of any group. Most opioid agonists were significantly more potent in decreasing response rate in males than females, and in GNDZ than SHAM rats; morphine and nalbuphine also increased response rate above control in some females. A pA2 analysis of naltrexone in combination with morphine suggested that there were no significant differences among groups in receptors at which morphine produced its discriminative stimulus effects. Although hormone replacement in GNDZ female rats at the end of the study reinstated estrous cycling, it did not substantially alter the ED50 for morphine discrimination. Thus, sex differences in potency of morphine as a discriminative stimulus may not be due to sex differences in gonadal hormone milieu. The possibility that sex differences in reinforcement frequency on morphine versus saline levers caused the sex differences in morphine discrimination is discussed.