Diverse roles for nitric oxide in synaptic signalling after activation of NMDA release-regulating receptors

NMDA receptors regulating transmitter release were studied in three model systems to investigate whether their activation involves the NO transduction system. In superfused slices of rat brain, the release of [3H]D-aspartate, [3H]noradrenaline and [3H]GABA evoked by NMDA could be modulated by nitrergic drugs. Tetrodotoxin (0.1 microM) exerted differential effects in the three systems indicative of the NMDA receptors (and hence sites of NO generation) being pre- or extra-synaptic, or a combination of both types of localization. L-Arginine (100 microM) enhanced NMDA-evoked release of [3H]GABA (110%), [3H]NA (120%) and [3H]D-ASP (700%). Exogenous NO donors could increase NMDA-induced release of [3H]NA and [3H]D-ASP from hippocampal slices, although differential effects were noted, whilst inhibitors of NO synthase (NG-nitro- and NG-amino-L-arginine, both 100 microM) attenuated (60-85%) the release. NMDA-evoked release of [3H]GABA from striatal slices were insensitive to exogenous NO donors, but NG-nitro- and NG-amino-L-arginine produced 100% increases. In all cases, the NMDA receptors regulating release are linked to a NO system, although the link to the receptors modulating release of [3H]GABA appeared different. The actions of the nitrergic drugs may depend upon the redox state and/or cellular milieu of the individual NMDA receptors involved.