NMDA receptor in nucleus accumbens is implicated in morphine withdrawal in rats

The purpose of the present study is to elucidate whether ketamine, a non-competitive antagonist of the NMDA receptor, can suppress the morphine withdrawal syndrome in rats at a dose without affecting motor functions and to identify its site of action in the central nervous system. Rats were made dependent on morphine by multiple injections of morphine hydrochloride for 5 days. They were then given ketamine at the following doses and routes of administration: (a) intraperitoneal (i.p.) injections (2-16 mg/kg), (b) intracerebroventricular (i.c.v.) injections (4-100 mug), and (c) intra-nucleus accumbens (NAc) or intra-amygdalar microinjections (0.4-10 mug). Naloxone HCl (1 mg/kg, i.p.) was administered 3 h after the last ketamine injection to precipitate withdrawal syndrome, which was scored within a period of 30 min. Results showed that some of the precipitated withdrawal signs were dose-dependently suppressed by repeated injections of ketamine at 8 and 16 mg/kg, i.p. or 100 mug, i.c.v. Dose-dependent suppression was observed by repeated microinjections (0.4-10 mug) of ketamine to NAc, but not to amygdala. These results indicate that the NMDA receptor antagonist ketamine has the ability to suppress morphine withdrawal syndrome in experimental settings without motor interference, and NAc could be the critical CNS site mediating such effect.