Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs

LD Snell and KM Johnson

In the present study, the authors found that, in Mg++-free buffer, N- methyl-D-aspartate (NMDA) was able to evoke the Ca++-dependent and tetrodotoxin-sensitive release of striatal acetylcholine (ACh), presumably via interaction with receptors on cholinergic interneurons. In Mg++-free buffer containing pargyline, NMDA also evoked a Ca++- dependent and tetrodotoxin-sensitive release of striatal [3H]dopamine (DA). Phencyclidine (PCP) and physiological concentrations of Mg++ (1.2 mM) also inhibited ACh release evoked by L-glutamate, L-aspartate and DL-homocysteate, but not ACh release evoked by the glutamate analogs quisqualate and kainate, suggesting that PCP is selective for the magnesium-sensitive, NMDA-preferring glutamate-aspartate receptor subtype. Comparison of PCP inhibition of NMDA-stimulated ACh and DA release with that produced by the competitive NMDA antagonist 2-amino-5- phosphonovalerate indicates that PCP is probably not altering release by a direct action on the NMDA recognition site. The ability of 2-amino- 5-phosphonovalerate, but not PCP, to prevent desensitization of NMDA- induced ACh release is consistent with this interpretation. Binding studies did, however, reveal a reduction in the apparent affinity of the PCP binding site by high concentrations of NMDA. This may suggest an allosteric link between the PCP-sigma receptor and the NMDA-type glutamate-aspartate receptor. The receptors mediating excitatory amino acid-induced DA release were somewhat less selective than those on cholinergic neurons in their sensitivity to both Mg++ and PCP. Structure-activity-relationship studies suggested that the inhibition off ACh and DA release evoked by NMDA involves biding to the PCP-sigma receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 238, Issue 3, pp. 938-946, 09/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics

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