Regulation of [3H]dopamine release from guinea pig striatum by NMDA receptor/channel activators and inhibitors

Document Type

Journal Article

Publication Date



Journal of Pharmacology and Experimental Therapeutics






Excitatory amino acids, that interact with the N-methyl-D-aspartate (NMDA) receptor stimulate release of [3H]dopamine ([3H]DA) from the striatum of the guinea pig and rat in a concentration-dependent manner. DA release was measured in the presence of domperidone and nomifensine to avoid complications associated with autoreceptor alteration of and reuptake of released DA. This release is inhibited by magnesium. Therefore, all experiments were performed in the absence of this ion. The competitive NMDA antagonists D-(-)2-amino-5-phosphonopentanoic acid and 3-[(±)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid and the noncompetitive antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine and phencyclidine also inhibit NMDA-stimulated release. Glycine enhances NMDA-stimulated release and can release [3H]DA in the absence of added NMDA. Release stimulated by glycine alone is not affected by 3-(±)-2-carboxypiperazine-4-yl]-propyl-1-phosphonic acid. Conversely, if the glycine antagonist 3-amino-1-hydroxy-2-pyrrolidone or 6-cyano-7-nitroquinoxaline-2,3-dione is included, NMDA elicits less release of [3H]DA. This inhibition can be overcome by increasing the concentration of glycine. The kappa-selective opioid agonist trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzene-acetamide is also capable of inhibiting the NMDA-stimulated release of [3H]DA from guinea pig and rat striatum. The mu agonist Tyr-D-Ala-Gly-(Me)Phe-Gly-ol and the delta agonist [D-Pen2-D-Pen5]enkephalin were unable to inhibit this release, in agreement with the opioid pharmacologic profile of these systems previously reported for potassium-stimulated [3H]DA release. These findings demonstrate the high degree of regulation that can be exerted upon the nigrostriatal dopaminergic system by excitatory amino acids and opioids.

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