Evidence that nitric oxide regulates the acute effects of ethanol on rat N-methyl-D-aspartate receptors in vitro.
Acute exposure to ethanol has been shown to inhibit the function of N-methyl-D-aspartate (NMDA) receptors (NMDAR). However, the mechanism by which ethanol produces inhibition of NMDAR and the factors that modulate this effect are not completely understood. Nitric oxide (NO) is an important modulator of NMDAR function in the hippocampus. Therefore, we examined the effects of NO donors on the ethanol-induced inhibition of NMDAR. Primary cultures of hippocampal neurons were prepared from postnatal day 3 rats. After 7 days in culture, NMDAR currents were recorded by using whole-cell patch-clamp electrophysiological techniques. Effects of acute exposure to ethanol on these currents were assessed in the absence and presence of NO donors. We found that the NO donors 1-hydroxy-2-oxo-3-(N-ethyl-2-aminoethyl)-e-ethyl-1-triazene (NOC-12, 100 microM) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 500 microM) inhibit currents gated by 100 microM NMDA plus 0.5 microM glycine. The inhibitory effect of NOC-12 on NMDAR currents could not be observed when 100 microM of the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) was present. Importantly, it was found that ethanol inhibits NMDAR responses to a significantly lesser extent in the presence of these donors. Ethanol (65 mM) inhibited NMDAR responses by 42+/-2%. In the presence of NOC-12 or SNAP, ethanol inhibited NMDAR responses by 21+/-4% and 11+/-7%, respectively. The effect of NOC-12 on ethanol's actions on NMDAR currents was blocked by PTIO. Our results suggest that NO is a novel modulator of the acute effects of ethanol on NMDAR function.
Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA. fvalenzuela@salud.unm.edu
Edmar T
ET
Costa
Vania M
VM
Ferreira
C Fernando
CF
Valenzuela
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004338:Drug Combinations; D000431:Ethanol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects
D004338:Drug Combinations; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D000431:Ethanol