Nitric oxide (NO) was first recognized as a messenger molecule in the central nervous system (eNS) in 1988 (52), when it was identified as the unstable intercellular factor that had been hypothesized, a year earlier (53), to mediate the increased cyclic GMP (cGMP) levels that occur on activation of glutamate receptors, particularly those of the NMDA (N-methyl-D-aspartate) subtype. The presence of an NO-forming enzyme (NO synthase, or NOS) in the brain was later confirmed (74), and this enzyme was subsequently purified (14) and its cDNA cloned and sequenced (12).

The discovery that NO functions as a signaling molecule in the brain opened a new dimension in our concept of neural communication, one overlaying the classical picture of chemical neurotransmission, where information is passed between neuronal elements at discrete loci (synapses), and in one direction, with a diffusive type of signal that disregards the spatial constraints on neu rotransmitter activity normally imposed by membranes, transporters, and in activating enzymes. In principle, NO could spread out from its site of produc tion to influence many different tissue elements (neuronal, glial, and vascular) that are not necessarily in close anatomical juxtaposition. During the past few years, much information on the enzymology and mo lecular characteristics of NO synthesis has accrued, as reviewed in other articles in this volume. Furthermore, data from immunocytochemistry, in situ hybridization, and NADPH diaphorase histochemistry have combined to give