BENZAMIDE, AN INHIBITOR OF POLY(ADP-RIBOSE) POLYMERASE, ATTENUATES METHAMPHETAMINE-INDUCED DOPAMINE NEUROTOXICITY IN THE C57B1 6N MOUSE/

Previous studies have indicated that the activation of poly(ADP-ribose ) polymerase (PARP), an enzyme involved in DNA plasticity-related phen omena, is an early event occurring in glutamate-induced neurotoxicity in vitro, and that inhibitors of PARP, including benzamide, are protec tive against both glutamate-and methamphetamine (METH)-induced neuroto xicity in vitro. To evaluate a central neuroprotective potential of be nzamide in vivo, the present study examined the effect of benzamide on the nigrostriatal dopamine toxicity (i.e. long-lasting striatal dopam ine depletion) induced by METH in the C57B1/6N mouse. Intraperitoneal injection of METH at 2-h intervals (4 injections of 5 mg/kg, 4 injecti ons of 10 mg/kg, or 2 injections of 20 mg/kg) dose-dependently reduced the levels of striatal dopamine in male C57B1/6N mice by up to 53% at 7 days post-treatment. Administration of benzamide (2 injections of 1 60 mg/kg spaced by a 4 h interval) during the different METH treatment protocols partially and significantly attenuated the METH-induced dop amine depletions. Benzamide (160 mg/kg i.p.) by itself had no acute ef fect on striatal dopamine metabolism and did not reduce body temperatu re. The concentrations of benzamide measured in the striatum at differ ent times following this same dose of drug were in a range (0.09-0.64 mM) reported in in vitro studies to be both neuroprotective and effect ive in inhibiting PARP activity. These results indicate a neuroprotect ive potential of benzamide in vivo and suggest a role of PARP in METH neurotoxicity.