Inhibition of nitric oxide release in vivo by ethanol

Objective: Previous studies indicate that the nitric oxide (NOcircle) pathway is involved in the acute or chronic effects of ethanol on the central nervous system. However, direct evidence for the effect of ethanol on NOcircle production in vivo is lacking, and it is not clear whether it is inhibition or stimulation of the NOcircle pathway that contributes to the behavioral effects of ethanol. Herein the release of NOcircle in the rat striatum in vivo in response to NMDA receptor activation-the dominant mechanism controlling NOcircle formation-has been investigated after systemic or local injections of ethanol. Methods: NMDA-induced release of authentic NOcircle was measured directly in the striatum of urethane-anesthetized (1.2 g/kg intraperitoneally) male Sprague-Dawley rats by using a direct-current amperometric method coupled to an electrically modified carbon microelectrode. An injector cannula was implanted in the proximity of the electrode (250 mum apart) for focal drugs application. Results: Local application of NMDA (1 mul, 100 muM) produced a sharp and transient NOcircle signal. Systemic ethanol, 1 or 2.5 g/kg intraperitoneally, caused a long-lasting, dose-dependent inhibition of NMDA-induced NOcircle release to 12.2 +/- 5.9 and 6.4 +/- 3.7% of control, respectively, 60 min after ethanol administration. Dizocilpine (0.5 mg/kg intraperitoneally) mimicked the ethanol effect, inhibiting NOcircle release to 1.6 +/- 0.66% of control. Local application of ethanol (1 mul, 2.5% v/v) in the striatum reduced the NMDA-induced response to 28.6 +/- 3.8% of control. Focal application of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (100 muM) or the nonselective NO synthase inhibitor L-W-nitro-arginine methyl esther (100 muM) also caused inhibition of NMDA-induced NOcircle release to 2.4 +/- 0.7 and 4.3 +/- 0.9% of control, respectively. Conclusions: Ethanol, at pharmacologically significant doses, strongly inhibits striatal NOcircle production and release apparently through inhibition of NMDA receptor function. Inhibition of NMDA receptor-mediated activation of the NOcircle pathway could be a primary neurobiological mechanism contributing to the effects of ethanol.