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Neurochemical Interactions of Competitive N-Methyl-D-Aspartate Antagonists with Dopaminergic Neurotransmission and the Cerebellar Cyclic GMP System: Functional Evidence for a Phasic Glutamatergic Control of the Nigrostriatal Dopaminergic Pathway

Authors


  • The present address of Dr. P. C. Contreras is CNS Diseases Research, G. D. Searle & Co., 4901 West Searle Parkway, Skokie, IL 60077, U.S.A.

  • The present address of Dr. P. L. Wood is Hoechst-Roussell Pharmaceuticals Inc., Somerville, NJ 08807-1258, U.S.A.

Address correspondence and reprint requests to Dr. T. S. Rao at CNS Diseases Research, G. D. Searle-Monsanto, Mail Zone AA 5E, 700 Chesterfield Village Parkway, St. Louis, MO 63198, U.S.A.

Abstract

Abstract: Direct intrastriatal injection of N-methyl-D-aspartate (NMDA; 100 μg/rat) increased striatal dopamine (DA) release in vivo. However, parenteral administration of (±)-3-(2-carboxypiperizin-4-yl)propyl-1-phosphonic acid (CPP) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) did not alter DA metabolism and release in several brain regions in the rat and mouse. Intracerebroventricular administration of the competitive NMDA antagonists CPP, CGS-19755, 2-amino-5-phosphonopentanoate, and 2-amino-7-phosphonoheptanoate did not alter rat striatal DA metabolism and release but profoundly reduced cerebellar cyclic GMP (cGMP) levels in the same animals. CPP and CGS-19755 decreased basal cerebellar cGMP levels in the mouse with ED50 values of 6 and 1 mg/kg, i.p., respectively. CPP antagonized the harmaline-induced increases in cGMP levels with an ED50 value of 5.0 mg/kg, i.p. CPP (25 mg/kg, i.p.) also decreased basal cGMP levels in mouse cerebellum for up to 3 h, a result suggesting brain bioavailability and a long duration of NMDA receptor antagonism in vivo. These contrasting patterns suggest that NMDA receptors exert a tonic excitatory tone on the guanine nucleotide signal transduction pathway in the cerebellum while exerting a phasic control over nigrostriatal dopaminergic neurotransmission. These results also indicate that competitive NMDA antagonists, unlike phencyclidine receptor agonists, may not mediate biochemical and behavioral effects via dopaminergic mechanisms.

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