Complex involvement of nitric oxide and cGMP at N-methyl- -aspartic acid receptors regulating γ-[H]aminobutyric acid release from striatal slices

Whilst the depolarization of postsynaptic N-methyl- -aspartic acid (NMDA) receptors leads to an influx of Ca²⁺ and subsequent synthesis of nitric oxide (NO), we examined roles for NO at striatal NMDA receptors regulating transmitter release. In superfused rat striatal slices, NMDA-evoked release of γ-³H]aminobutyric acid (³H]GABA) was investigated in the presence of nitrergic drugs. NMDA-induced release of ³H]GABA was attenuated by -2-aminophosphonopentanoate, tetrodotoxin and omission of Ca²⁺. -Arginine enhanced NMDA-evoked release of ³H]GABA, but exogenous NO donors were ineffective. Inhibitors of NO synthase (N^G-nitro- and N^G-amino- -arginine) and guanylate cyclase (LY83583) elevated release. Since NMDA-evoked release of ³H]GABA was partially tetrodotoxin-sensitive, nitrergic-linked NMDA receptors regulating the release are both pre- and extrasynaptic. Thus not only does NO arise from multiple sites, and involve NMDA receptors with their redox site insensitive to exogenous NO donors, but the NMDA receptors are under the influence of nitrergic and cGMP-linked negative feedback mechanisms.