Competitive and glycine/NMDA receptor antagonists attenuate withdrawal-induced behaviours and increased hippocampal acetylcholine efflux in morphine-dependent rats

The present study has examined the glycine/N-methyl-D-aspartate (NMDA) receptor antagonist, R-(+)-3-amino-1-hydroxqpyrrolid-2-one (R-(+)-HA-966) and the competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)piperidine-2-carboxyl acid (CGS 19755) on the behavioural syndrome and increased hippocampal acetylcholine efflux induced during morphine-withdrawal in the rat. Subcutaneous naltrexone (1 mg/kg) injection, 48 hr after implantation of a 75 mg morphine pellet, induced a robust withdrawal syndrome consisting of wet dog shakes, ejaculations, mouth movements, ptosis, irritability to touch and diarrhoea. Pretreatment with the alpha(2)-adrenoceptor agonist, clonidine (0.1-0.4 mg/kg), R-(+)HA-966 (10-60 mg/kg) or CGS 19755 (5 or 10 mg/kg) significantly reduced the incidence of withdrawal behaviours. In addition, all three compounds significantly attenuated the increase in hippocampal acetylcholine efflux induced following naltrexone (1 mg/kg, s.c.) injection in morphine-dependent rats. These results provide further evidence demonstrating that NMDA receptor antagonists attenuate both the behavioural and neurochemical effects observed during morphine withdrawal in the rat. (C) 1997 Elsevier Science Ltd.