NMDA Receptor Blockade Increases In Vivo Striatal Dopamine Synthesis and Release in Rats and Mice with Incomplete, Dopamine‐Depleting, Nigrostriatal Lesions

Abstract

The role of excitatory amino acids (EAAs) in the regulation of striatal dopamine (DA) synthesis and release in rats and mice with incomplete DA-depleting lesions of the nigrostriatal system was investigated using in vivo microdialysis in rats and estimates of striatal in vivo tyrosine hydroxylase activity in mice. Dopaminergic nigrostriatal input to the striatum was partially lesioned in rats with stereotactic perinigral 6-hydroxydopamine injections and in C57BL mice with systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. In rats, addition of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5, 10 mM) to dialysate increased local striatal DA release and synthesis. In 6-hydroxydopamine partially lesioned rats, the effects of AP-5 on DA release were significantly diminished, and AP-5 had no significant effect on DA synthesis. Perfusion with the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 1 mM) alone increased DA synthesis slightly, whereas DNQX + AP-5 (10 mM) increased DA synthesis to levels comparable with those observed with AP-5 alone. Local striatal DA synthesis was also increased by addition of the NMDA receptor antagonist (+/-)-3-(2-carboxypiperizin-4-yl)propyl-1-phosphonic acid (CPP, 1 mM) to the perfusion buffer. Local inhibition of nitric oxide synthase with nitro-L-arginine (10 mM) perfused through the striatal microdialysis probe did not alter DA synthesis, suggesting that the effects observed with NMDA receptor blockade are not mediated by nitric oxide. In unlesioned mice, none of the systemically injected EAA receptor antagonists altered striatal DA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)