NAALADase inhibition reduces alcohol consumption in the alcohol-preferring (P) line of rats

N-acetyl-aspartyl-glutamate (NAAG) is a major peptide component of the brain, with millimolar tissue levels of 0.1-5 nmol/mg wet weight. NAAG is hydrolyzed by the enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase; glutamate carboxypeptidase II; EC no. 3.4.17.21) to N-acetyl-aspartate (NAA) and glutamate. Recently, a potent and selective NAALADase inhibitor termed 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was identified that has a 300 pM Ki for NAALADase inhibition. Given the accumulating evidence indicating an important role of the glutamate system in alcoholism and dependence, the objective of this study was to evaluate the effects of systemic administration of 2-PMPA (50, 100 and 200 mg/kg; i.p.) upon the ethanol intakes of alcohol-preferring (P) rats. Female P rats (n = 8) received daily 1-hour scheduled access to a 10% (v/v) ethanol. In a within-subjects design, 2-PMPA treatments were tested once a week. Baseline ethanol drinking consisted of the mean of the 3 days prior to testing in which saline injections were given. Results indicated that, whereas the 200 mg/kg dose of 2-PMPA had no effect on ethanol intake, both the 50 and 100 mg/kg doses significantly reduced ethanol consumption by approximately 25% (p < 0.05) during the 1-hour access period. Body weights and 24-hour water intakes were not altered at any of the doses. These data suggest that the NAAG/NAALADase system may be involved in neuronal systems regulating alcohol-drinking behavior.