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NMDA Receptor Blockade Increases In Vivo Striatal Dopamine Synthesis and Release in Rats and Mice with Incomplete, Dopamine‐Depleting, Nigrostriatal Lesions
Author(s) -
Richard Matthew G.,
Bennett James P.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64052080.x
Subject(s) - dnqx , microdialysis , nmda receptor , dopamine , nigrostriatal pathway , medicine , endocrinology , chemistry , tyrosine hydroxylase , dopaminergic , striatum , receptor antagonist , glutamate receptor , substantia nigra , antagonist , biology , receptor , ampa receptor , biochemistry
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 m M ) 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 m M ) alone increased DA synthesis slightly, whereas DNQX + AP‐5 (10 m M ) 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 m M ) to the perfusion buffer. Local inhibition of nitric oxide synthase with nitro‐ l ‐arginine (10 m M ) 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. In MPTP‐treated mice with partial nigrostriatal lesions, treatment with the competitive NMDA receptor antagonist CPP (5 mg/kg i.p.) increased DA synthesis significantly compared with lesioned mice injected with vehicle. Our results suggest that EAAs mediate a tonic inhibition of DA terminal activity in the striatum via NMDA receptors and that this suppressive signal is reduced in animals with partial destruction of the nigrostriatal pathway.