Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release.

It has been reported that kappa-opioids produce greater analgesia in women than in men. Sex differences are also apparent in drug-induced behaviors. Repeated administration of cocaine (25 mg/kg) produced a greater locomotor and sensitization response in C57BL/6By female mice. It was examined whether the increased sensitization in females to repeated cocaine administration was related to differences in kappa-opioid responses. The effects of the kappa agonist U62066 (spiradoline mesylate) on cocaine-induced locomotor stimulation in vivo and NMDA-mediated dopamine release in vitro were measured. In male, but not female mice, U62066 (1 mg/kg) given 30 min before cocaine potentiated the locomotor stimulation of an acute cocaine administration. U-62066 did not affect the development of locomotor sensitization with repeated cocaine administration (25 mg/kg s.c., once daily for 3 days), and a further enhanced response was not seen on days 2 and 3. It was then examined whether dopamine release, measured in vitro, plays a role in sex dependent differences in kappa-opioid- or NMDA-modulated dopaminergic function. In tissue perfusion studies, the in vitro NMDA (25 microM)-evoked release of labelled dopamine from striatum was lower in females (fractional release = 5.4 +/- 0.4 and 4.0 +/- 0.4 in male and female mouse striatum). U62066 (1 microM) and ibogaine (1 microM), an indole alkaloid claimed to be useful in the treatment of drug addiction that acts in part at the kappa-opioid receptor, both reduced the NMDA (25 microM)-evoked release of dopamine. Inhibition of the release was significantly greater in tissue from male mice. Prior in vivo cocaine administration did not alter the NMDA-evoked dopamine release. Our studies indicate that kappa-opioid and NMDA receptor activity show differences between female and male mice that may account for differences in cocaine-induced behaviors, but do not exclude the role of other hetereoceptors modulating dopamine release.