Excitotoxic action of NMDA agonists on nigrostriatal dopaminergic neurons: modulation by inhibition of nitric oxide synthesis

Brain Research
B P ConnopR J Beninger

Abstract

Focal infusions of N-methyl-D-aspartate (NMDA) or an endogenous NMDA agonist, quinolinic acid (QUIN), into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a dose-dependent depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity, a biochemical marker for dopaminergic neurons. To assess the intermediary role of nitric oxide in the neurotoxicity elicited by these toxins, their 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 onset 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% inhibition of cerebellar and nigral NOS activity, respectively. Intranigral infusion of 40 and 60 nmol QUIN reduced ipsilateral striatal TH activity by 62 and 75%, respectively. However, 40 and 60 nmol QUIN infusions into animals pretreated with L-NAME (250 mg/kg) reduced...Continue Reading

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