Inhibition of nitric oxide release in vivo by ethanol.
OBJECTIVE
Previous studies indicate that the nitric oxide (NO(.)) 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 NO(.) production in vivo is lacking, and it is not clear whether it is inhibition or stimulation of the NO(.) pathway that contributes to the behavioral effects of ethanol. Herein the release of NO(.) in the rat striatum in vivo in response to NMDA receptor activation--the dominant mechanism controlling NO(.) formation-has been investigated after systemic or local injections of ethanol.


METHODS
NMDA-induced release of authentic NO(.) 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 microm apart) for focal drugs application.


RESULTS
Local application of NMDA (1 microl, 100 microM) produced a sharp and transient NO(.) signal. Systemic ethanol, 1 or 2.5 g/kg intraperitoneally, caused a long-lasting, dose-dependent inhibition of NMDA-induced NO(.) 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 NO release to 1.6 +/- 0.66% of control. Local application of ethanol (1 microl, 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 microM) or the nonselective NO synthase inhibitor L-N(G)-nitro-arginine methyl esther (100 microM) also caused inhibition of NMDA-induced NO(.) release to 2.4 +/- 0.7 and 4.3 +/- 0.9% of control, respectively.


CONCLUSIONS
Ethanol, at pharmacologically significant doses, strongly inhibits striatal NO(.) production and release apparently through inhibition of NMDA receptor function. Inhibition of NMDA receptor-mediated activation of the NO(.) pathway could be a primary neurobiological mechanism contributing to the effects of ethanol.
Rossetti
Zvani L
ZL
Department of Neuroscience and CNR Institute of Neuroscience, University of Cagliari, Cittadella di Monserrato, 09042 Monserrato, Italy. rossetti@unica.it
Crespi
Francesco
F
D000818:Animals; D000431:Ethanol / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D000431:Ethanol; D019331:NG-Nitroarginine Methyl Ester