title: Novel uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist MRZ 2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure.
abstract: Previous findings suggested that drugs modulating glutamatergic neurotransmission could be useful in the treatment of alcohol dependence. This study examined 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-methyl-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 treatment 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 weeks later in the absence of the drug. In a second experiment long-term ethanol-experienced rats trained in an operant free-choice ethanol self-administration 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 during the ADE. In an additional experiment, MRZ 2/579 (0.5-4 mg/kg i.p.) was tested for generalization to the ethanol cue in a drug discrimination procedure. Chronic MRZ 2/579 treatment selectively abolished the increased ethanol 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 effect on lever pressing for ethanol, but not for water, both during the ADE and basal drinking. MRZ 2/579 dose dependently generalized to the ethanol cue in the drug discrimination experiment. It is concluded that MRZ 2/579 might exert its reducing effect on ethanol intake by substituting for some of the stimulus properties of ethanol.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany. hoelter@mpipsykl.mpg.de
authors.forename: S M
authors.initials: SM
authors.lastname: Hölter
authors.forename: W
authors.initials: W
authors.lastname: Danysz
authors.forename: R
authors.initials: R
authors.lastname: Spanagel
mesh_terms: D000428:Alcohol Drinking / Q000517:prevention & control*; D000818:Animals; D003517:Cyclopentanes / Q000032:analysis / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012646:Self Administration / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D003517:Cyclopentanes; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C114144:neramexane