Sex Differences in Sensitivity to the Depressive-like Effects of the Kappa Opioid Receptor Agonist U-50488 in Rats

Background: Dynorphin, an endogenous ligand at kappa opioid receptors (KORs), produces depressive-like effects and contributes to addictive behavior in male nonhuman primates and rodents. Although comorbidity of depression and addiction is greater in women than men, the role of KORs in female motivated behavior is unknown. Methods: In adult Sprague-Dawley rats, we used intracranial self-stimulation to measure effects of the KOR agonist (+/-)-trans-U-50488 methanesulfonate salt (U-50488) (.0-10.0 mg/kg) on brain stimulation reward in gonadally intact and castrated males and in females at estrous cycle stages associated with low and high estrogen levels. Pharmacokinetic studies of U-50488 in plasma and brain were conducted. Immunohistochemistry was used to identify sex-dependent expression of U-50488-induced c-Fos in brain. Results: U-50488 dose-dependently increased the frequency of stimulation (threshold) required to maintain intracranial self-stimulation responding in male and female rats, a depressive-like effect. However, females were significantly less sensitive than males to the threshold-increasing effects of U-50488, independent of estrous cycle stage in females or gonadectomy in males. Although initial plasma concentrations of U-50488 were higher in females, there were no sex differences in brain concentrations. Sex differences in U-50488-induced c-Fos activation were observed in corticotropin releasing factor-containing neurons of the paraventricular nucleus of the hypothalamus and primarily in non-corticotropin releasing factor-containing neurons of the bed nucleus of the stria terminalis. Conclusions: These data suggest that the role of KORs in motivated behavior of rats is sex-dependent, which has important ramifications for the study and treatment of mood-related disorders, including depression and drug addiction in people.