Drugs of abuse, Alcohol, Striatum, Nucleus accumbens Nitric oxide (NO), a labile free-radical gas, is known to be a n important messenger in several cell systems, including endothelial cells, macrophages, and neurons. In brain, the particular uniqueness of NO as a biological messenger has expanded current concepts of synaptic neurotransmission (Dawson and Snyder, 1994). NO is synthesized from L-arginine by the enzyme, nitric oxide synthase (NOS), of which there are three known forms: neuronal, inducible, and endothelial (for review, see Dawson and Snyder, 1994). NOS and NO have been shown to regulate neurotransmitter release and reuptake (Pogun et al., 1994; Zhu and Luo, 1992) and have been implicated in a variety of physiological functions including long-term potentiation and other NMDA-glutamate receptor-mediated responses (Schuman and Madison, 1991), analgesia (Meller and Gebhart, 1993), and opioid tolerance (Babey et al., 1994). Under conditions of excessive production, NOalso may be neurotoxic (Dawson et al., 1993).
While there is increasing knowledge about the shortterm regulation of neuronal NOS (e.g., phosphorylationdependent changes in catalytic activity; for review, see Dawson and Snyder, 1994), little is known about the more long-term regulatory processes that presumably require changes in NOS protein levels. Since NO is a labile, diffusible gas that is not stored in synaptic vesicles, it would seem that changes in the amount of NOS would be one critical determinant of NO availability at the synapse. Based on the important role played by adaptations in signal transduction pathways in the chronic actions of drugs of abuse (see Nestler et al., 1993), we chose to examine the regulation of NOS following chronic ethanol ingestion. Previous work has shown that ethanol can acutely block NMDA channel function, whereas chronic exposure can lead to a compensatory enhancement of NMDA receptor channel expression and function (e.g.