EXCITOTOXIC ACTION OF NMDA AGONISTS ON NIGROSTRIATAL DOPAMINERGIC-NEURONS - MODULATION BY INHIBITION OF NITRIC-OXIDE SYNTHESIS

Focal infusions of N-methyl-D-aspartate (NMDA) or an endogenous NMDA a gonist, quinolinic acid (QUIN), into the substantia nigra pars compact a (SNc) of adult Sprague-Dawley rats resulted in a dose-dependent depl etion of ipsilateral striatal tyrosine hydroxylase (TH) activity, a bi ochemical marker for dopaminergic neurons. To assess the intermediary role of nitric oxide in the neurotoxicity elicited by these toxins, th eir action was tested in animals treated with N-omega-nitro-L-arginine methyl ester (L-NAME). Systemic injections (2 injections; 8 h apart) of L-NAME (100, 150 and 250 mg/kg) produced a dose-related inhibition of cerebellar nitric oxide synthase (NOS) activity. The time-course of cerebellar NOS inhibition following L-NAME (250 mg/kg) was rapid in o nset and lasted for at least 24 h following the second injection. An L -NAME treatment regimen of 250 mg/kg, with the second injection given 24 h prior to assessment of NOS activity, produced an 87 and 91% inhib ition of cerebellar and nigral NOS activity, respectively. Intranigral infusion of 40 and 60 nmol QUIN reduced ipsilateral striatal TH activ ity by 62 and 75%, respectively. However, 40 and 60 nmol QUIN infusion s into animals pretreated with L-NAME (250 mg/kg) reduced striatal TH activity by 83 and 96%, respectively. Intranigral infusion of 15 and 3 0 nmol NMDA produced a 48 and 77% decrease in striatal TH activity, re spectively, whereas the same doses of NMDA given to animals pretreated with L-NAME (250 mg/kg) resulted in a 59 and 88% decrease in TH activ ity. Thus, both QUIN and NMDA toxicity was enhanced following L-NAME p retreatment. The destruction of the nigrostriatal pathway was verified using TH immunocytochemistry of the SNc. It was also observed that a low dose of L-NAME (1.5 mg/kg), previously shown to be neuroprotective in cerebral ischemic damage, did not influence NMDA (15 nmol) neuroto xicity. The results of this study show that extensive inhibition of NO S activity enhances NMDA receptor-mediated excitotoxicity.