Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat

It has been repeatedly reported that NMDA receptors may contribute to ethan ol-induced discriminative stimulus effects and withdrawal syndrome, However , the role of NMDA receptors in the reinforcing properties of ethanol remai ns unclear. The aim of the present study was to evaluate effects of the nov el low-affinity, uncompetitive NMDA receptor antagonist. 1-amino-1,3,3,5,5- pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administ ration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure. for ced treatment with high doses (9-15 g/kg/day) was used to induce physical d ependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drin king behaviour in a maintenance phase of ethanol self-administration. In co ntrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a prog ressive decrease in operant responding for ethanol. MRZ 2/579 (0.5-7.5 mg/k g, i.p.) and another low-affinity NMDA receptor antagonist, memantine(1-10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with e fficacies comparable with that of a standard benzodiazepine derivative, dia zepam. The results of the present study indicate that: (i) intermittent adm inistration of MRZ 2/579 may lead to a gradual decrease of operant respondi ng for ethanol: and (ii) the group of low-affinity uncompetitive NMDA recep tor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal. (C) 2001 Elsevier science B.V. All rights reserved.