Inhibition of kappa opioid receptors attenuated increased cocaine intake in rats with extended access to cocaine

Previous studies demonstrated that the dynorphin/kappa opioid system was up-regulated upon repeated cocaine self-administration. In the present study, we tested the hypothesis that increased cocaine self-administration with extended access was associated with increased activity of the kappa opioid system in rats. Rats self-administered 0.5 mg/kg per injection of cocaine on a fixed-ratio (FR) schedule in either 1-h (short access, ShA) or 6-h (long access, LgA) sessions. After cocaine intake in the LgA rats increased to a maximum, the effects of kappa opioid receptor antagonists and a partial agonist were tested on cocaine intake in ShA and LgA rats. Cocaine self-administration increased under FR and progressive-ratio (PR) schedules in LgA rats. Nor-BNI (15-30 mg/kg), a kappa receptor antagonist, decreased cocaine intake in LgA rats under a PR schedule (ShA, +1.7%; LgA, -27.4% from baseline), whereas naltrexone (0.3-10 mg/kg) and SG-II-49 (0.025-0.1 mg/kg), a nonspecific opioid receptor antagonist and a partial agonist, respectively, decreased cocaine intake in both groups (PR data: SG-II-49, ShA -28.6%, LgA -19.8%; naltrexone, ShA -34.6%, LgA -11.8% compared with vehicle data). The present study demonstrated that the antagonism of kappa opioid receptors attenuated only the increased cocaine intake in LgA rats under a PR schedule, whereas the antagonism of A mu and kappa receptors decreased cocaine intake in both ShA and LgA groups. The data suggest that increased motivation for cocaine in rats with extended access may be related to increased kappa opioid activity and may contribute to compulsive use.