Nitric Oxide and Long-Term Habituation to Novelty in the Rat" zy M. PAPA: M. P. PELLICANO? AND A. G. SADILEC*d bInstituteof Human Anatomy Second University of Naples 80138 Naples, Italy CLaboratoty of the Neurophysiology of Behavior and Neural Networks Department of Human Physiology zyxw '%: Bottaui " Second University of Naples Constantinopoli 16 80138 Naples, Italy zyxw INTRODUCTION Nitric oxide (NO) is thought to be an intracellular messenger or neurotransmitter in the central nervous system'** that is made from the amino acid L-arginine by the enzyme nitric oxide synthase (NOS) through the activation of the N-methyla- aspartate (NMDA) subtype of glutamate receptors in a Ca2+-dependent manner. In fact, Ca2+ ions activate NOS by binding a calmodulin subregion of the enzyme.3NO diffuses transcellularly to enter adjacent neurons or astrocytes to bind the heme ring of the soluble form of guanylylcyclase thus increasing the cytosolic concentration of cyclic guanosine monophosphate (cGMP) [see for a review reference zyx 41. The enzyme NOS is present in endothelial cells, macrophages, and neurons in different isoforms. The neuronal isoform is of the constitutive noninducible type and has been shown only in a small number of neurons2 NO is thought to be involved in a variety of processes including synaptic transmission, cerebral blood flow, and excitotoxicity [see for a review, e.g., reference 51. Neuronal nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) is known to be a NOS enzyme per se,3.6 and the high correlation between NOS and NADPH-d has been shown in ganglion cells of the guinea-pig intestine.' The aim of this research was twofold, (i) to map the neural consequences of exposure to spatial novelty in the rat brain by histochemistry for NADPH-d; and (ii) to test the role of nitric oxide in the formation of long-term habituation (LTH) by inhibiting NOS activity by N6-nitro-L-arginine (L-NOARG). The behavioral task used here has been shown to be sensitive to a series of manipulations during the postexposure period, as it requires activation of the immediate early genes (IEG) c-fos and c-jun,K DNA remodeling,' polysome aggrega- tion, protein synthesis, an intact hippocampus and neocortex, and both the slow wave and paradoxical sleep phases.'" Further, it is modulated by NMDA receptors11J2 and by endogenous or exogenous vasopressin, but not by endogenous opioids.I3 In addition, lesion studies indicate that zyxw LTH is modulated by the dorsal noradrenergic efferents of the locus c o e r ~ l e u s ~ ~ that innervate the entire forebrain,15J6 and by the @I'his work was supported by a trilateral project CNR 92.01092.CT04 and by MURST 40% dTo whom correspondence should be addressed. grants. 316