NEUROTOXICITY IN CONSCIOUS RATS FOLLOWING INTRAVENTRICULAR SNAP, A NITRIC-OXIDE DONOR

A solution containing S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO.-releasing compound, was microinjected in doses of 0.25-2 mu mol into a lateral ventricle of conscious rats. SNAP produced dose-dependent convulsions similar to those associated with limbic stimulation, such as tonic extension of the hindlimbs and tail, and dystonia of the forepaws. At 2 mu mol, SNAP evoked hyperventilation (arterial hypocapnia), arterial hyperglycemia and caused necrotic lesions of periventricular gray (e.g. lateral septal nucleus) and white matter structures. In the caudate nucleus and lateral septal nucleus ipsilateral to injection, SNAP elicited a bipolar metabolic pattern of low glucose metabolism proximal to the ventricle with higher values occurring more distally. In control studies, we proved that the residue of SNAP decomposition, N-acetylpenicillamine disulfide injected intraventricularly (2 mu mol), was without physiological, behavioral, or histological effects. Ventricular pretreatment with methylene blue (2 nmol), a putative inhibitor of guanylate cyclase and superoxide generator, suppressed several of the behavioral manifestations of 1 mu mol SNAP, such as the forepaw dystonia, squinting, and facial clonus, but was ineffective on the physiological and histological variables affected by the 2 mu mol SNAP dose. Another NO. donor, sodium nitroprusside (2 mu mol), produced fewer behavioral and cytotoxic effects over a 55-min observation period, but caused more intense and widely distributed metabolic stimulation, especially in commissural and projection white matter tracts. The results are the basis for a conscious rat model using intraventricular injection of nitrocompounds to examine the physiological, behavioral, metabolic and cytotoxic properties of NO. in the brain.