Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo:: Role of ionotropic glutamate receptor-dependent mechanisms

We have investigated the influence of the nitric oxide synthase (NOS) substrate, NG-hydroxy-L arginine (H-ARG) on dopamine (DA) and glutamate (GLU) efflux in vivo using concentric microdialysis probes implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion of H-ARG (100 mu M, 200 mu M, or 1 mM for 120 min) increased DA efflux in a dose-dependent fashion. The facilitatory effect of H-ARG (1 mM) on DA efflux was abolished following pretreatment (80 min) with the constitutive NOS inhibitor 7-nitroindazole (7-NI, 10 mu M) but unaffected by L-N-G(1-iminoethyl) lysine (100 mu M) infusion. As both H-ARG (1 mM) and the NO-generator (+/-)-S-nitroso-N-acetylpenicillamine (1 mM) were observed to increase GLU efflux concurrently with the effect on DA efflux, we evaluated the potential intermediary role of GLU in NO-facilitated DA efflux using ionotropic GLU receptor antagonists. Local infusion of dizocilpine maleate (10 mu M) or (+/-)-2-amino-3-[3-(carboxymethoxy)-5-methyl-isoxazol-4-yl] propionic acid (100 mu M), attenuated the H-ARG (1 mM)-induced elevation of extracellular DA levels. Conversely, similar treatment with the kainate receptor antagonist d-gamma-glutamyl-aminomethanesulfonic acid did not alter H-ARG-induced DA efflux. To evaluate the regulatory influence of striatal NO on NMDA receptor activation, NMDA (100 mu M) was co-perfused with either H-ARG (2 mM) or 7-NI(10 mu M). While co-perfusion with 7-NI potentiated NMDA induced DA efflux. similar treatment with H-ARG (2 mM) abolished the effect. These results demonstrate that endogenous NO production stimulated via H-ARG-dependent activation of type 1 NOS, enhances striatal DA efflux via an increase in glutamatergic tone on ionotropic GLU-receptors. At higher levels of NOS activation (following H-ARG (2 mM) or NMDA infusion), NO may block glutamatergic neurotransmission via inhibition of NMDA receptor function. (C) 1998 Elsevier Science Ltd. All rights reserved.