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 phenomena, is an early event occurring in glutamate-induced neurotoxicity in vitro, and that inhibitors of PARP, including benzamide, are protective against both glutamate- and methamphetamine (METH)-induced neurotoxicity in vitro. To evaluate a central neuroprotective potential of benzamide in vivo, the present study examined the effect of benzamide on the nigrostriatal dopamine toxicity (i.e. long-lasting striatal dopamine depletion) induced by METH in the C57B1/6N mouse. Intraperitoneal injection of METH at 2-h intervals (4 injections of 5 mg/kg, 4 injections 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 160 mg/kg spaced by a 4 h interval) during the different METH treatment protocols partially and significantly attenuated the METH-induced dopamine depletions. Benzamide (160 mg/kg i.p.) by itself had no acute effect on striatal dopamine metabolism and did not reduce body temperature. The concentrations of benzamide measured in the striatum at different 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 effective in inhibiting PARP activity. These results indicate a neuroprotective potential of benzamide in vivo and suggest a role of PARP in METH neurotoxicity.     

Effects of l-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey

We studied the effects of

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-DOPA on the firing patterns of pallidal neurons in experimental parkinsonism. After a unilateral injection of MPTP, we observed a decrease in the firing rate of GPe neurons, and a slight increase in their bursting activity. In the GPi, there was a considerable augmentation of both neuronal firing frequency and the number of bursting cells. During

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-DOPA treatment (10 mg/kg), GPe neurons.pattern is almost unmodified. The firing frequency of GPi neurons, on the contrary, decreased even lower than the control level. A slight reduction was observed in bursting activity. These unexpected results would show that the normalizing effect of

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-DOPA on GPi output is limited.