Novel uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist MRZ2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure

Previous findings suggested that drugs modulating glutamatergic neurotransm ission could be useful in the treatment of alcohol dependence. This study e xamined the effects of chronic and acute treatment with MRZ 2/579 (1-amino- 1,3,3,5,5-pentamethyl-cyclohexane hydrochloride), a novel uncompetitive N-m ethyl-D-aspartate receptor antagonist, on voluntary ethanol intake in long- term ethanol-experienced rats. Rats were implanted with mini-osmotic pumps delivering either 9.6 mg/day MRZ 2/579 or vehicle, and the effects of treat ment on the alcohol deprivation effect (ADE) were studied in a four-bottle home cage-drinking paradigm. The same rats were tested for a second ADE 3 w eeks later in the absence of the drug. In a second experiment long-term eth anol-experienced rats trained in an operant free-choice ethanol self-admini stration paradigm with concurrent water received acute MRZ 2/579 treatment (0-4 mg/kg i.p.) before a 23-h session either during basal drinking or duri ng the ADE. In an additional experiment, MRZ 2/579 (0.5-4 mg/kg i.p.) was t ested for generalization to the ethanol cue in a drug discrimination proced ure. Chronic MRZ 2/579 treatment selectively abolished the increased ethano l intake during the ADE. This effect depended on the presence of the drug. Acute MRZ 2/579 treatment (2 and 4 mg/kg) had a short-lasting reductive eff ect on lever pressing for ethanol, but not for water, both during the ADE a nd basal drinking. MRZ 2/579 dose dependently generalized to the ethanol cu e in the drug discrimination experiment. It is concluded that MRZ 2/579 mig ht exert its reducing effect on ethanol intake by substituting for some of the stimulus properties of ethanol.