Regulation of neurotransmitter release by endogenous nitric oxide in striatal slices.

This study sought to determine the potential role of nitric oxide (NO) in N-methyl-D-aspartate (NMDA)-stimulated efflux of [14C] gamma-aminobutyric acid (GABA) and [3H]acetylcholine from striatal slices in vitro. In Mg2+-free buffer, NMDA-stimulated [14C]GABA and [3H]acetylcholine release were inhibited by the guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and, to a lesser extent, by the nitric oxide synthase inhibitor, nitroarginine (N-Arg). Since reversal of catecholamine transporters previously has been implicated in the mechanism underlying NO-induced catecholamine release, we used the GABA transport inhibitor, 1-(2-(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-py ridine-carboxylic acid hydrochloride (NNC-711), to address the role of GABA transport in NArg-sensitive NMDA-induced release. NNC-711 inhibited NMDA-stimulated [14C]GABA efflux by 50%, confirming our previous report that NMDA-stimulated GABA release is partially dependent on reversal of the transporter. The effect of N-Arg in the presence of NNC-711 was similar to its effect in the absence of the transport inhibitor, suggesting that reversal of the transporter is not involved in the NO component of NMDA-stimulated [14C]GABA release. These data suggest that glutamatergic transmission through striatal NMDA receptors is partially mediated through activation of the NO/guanylate cyclase pathway and that this mechanism may contribute to the tetrodotoxin sensitivity of NMDA-induced release of GABA and acetylcholine in the striatum.