Effects of repeated kappa-opioid receptor agonist U-50488 treatment and subsequent termination on intracranial self-stimulation in male and female rats.

Repeated drug administration results in sensitization, tolerance, or no change in subsequent drug-induced alterations of motivated behaviors, such as intracranial self-stimulation (ICSS). For example, repeated mu-opioid agonist administration results in increased expression of mu agonist-induced facilitation of ICSS. Acute kappa-opioid receptor (KOR) agonist administration depresses ICSS; however, effects of repeated KOR agonist administration on ICSS are unknown. This study determined effects of daily KOR agonist U-50488 administration and subsequent termination on ICSS in male and female rats. Female (n = 5) and male (n = 6) Sprague-Dawley rats were trained to respond for electrical brain stimulation under a frequency-rate ICSS procedure. Sequential U-50488 dose-effect functions (1-5.6 mg/kg, intraperitoneal) were determined every 7 days over a 21-day experimental period during which saline and increasing U-50488 doses (3.2-5.6 mg/kg, intraperitoneal) were administered on intervening days. Sequential U-50488 dose-effect functions were also determined 7 and 28 days after termination of repeated U-50488 administration. U-50488 dose-dependently depressed ICSS in both female and male rats. There were no sex differences on either initial or repeated U-50488 treatment effects. Repeated 5.6 mg/kg U-50488 administration produced selective tolerance to the rate-decreasing, but not threshold-altering, effects of 5.6 mg/kg U-50488 during sequential dose-effect test sessions. Neither repeated U-50488 administration nor termination of U-50488 significantly altered baseline ICSS. Overall, these results suggest neither tolerance nor sensitization develops to the depressive-like effects of repeated KOR agonist activation. Selective tolerance to the rate-decreasing effects of repeated KOR agonist administration may have implications for elucidating the neurobiological processes involved in long-term abused drug self-administration.