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 brai n, with millimolar tissue levels of 0.1-5 nmol/mg wet weight. NAAG is hydro lyzed by the enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase ; glutamate carboxypeptidase II; EC no. 3.4.17.21) to N-acetyl-aspartate (N AA) and glutamate. Recently, a potent and selective NAALADase inhibitor ter med 2-(phosphonomethyl)pentane-dioic acid (2-PMPA) was identified that has a 300 pM Ki for NAALADase inhibition. Given the accumulating evidence indi cating an important role of the glutamate system in alcoholism and dependen ce, the objective of this study was to evaluate the effects of systemic adm inistration of 2-PMPA (50, 100 and 200 mg/kg; i.p.) upon the ethanol intake s of alcohol-preferring (P) rats. Female P rats (n = 8) received daily 1-ho ur scheduled access to a 10% (v/v) ethanol. In a within-subjects design, 2- PMPA treatments were tested once a week. Baseline ethanol dr inking consist ed of the mean of the 3 days prior to testing in which saline injections we re 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-ho ur access period. Body weights and 24-hour water intakes were not altered a t any of the doses. These data suggest that the NAAG/NAALADase system may b e involved in neuronal systems regulating alcohol-drinking behavior.