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 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 striatal TH activity by 83 and 96%, respectively. Intranigral infusion of 15 and 30 nmol NMDA produced a 48 and 77% decrease in striatal TH activity, respectively, 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 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Connop
B P
BP
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Boegman
R J
RJ
Jhamandas
K
K
Beninger
R J
RJ
D000594:Amino Acid Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology*
D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016202:N-Methylaspartate; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D017378:Quinolinic Acid; D019331:NG-Nitroarginine Methyl Ester