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 m u mol into a lateral ventricle of conscious rats. SNAP produced dose-d ependent convulsions similar to those associated with limbic stimulati on, such as tonic extension of the hindlimbs and tail, and dystonia of the forepaws. At 2 mu mol, SNAP evoked hyperventilation (arterial hyp ocapnia), arterial hyperglycemia and caused necrotic lesions of perive ntricular gray (e.g. lateral septal nucleus) and white matter structur es. In the caudate nucleus and lateral septal nucleus ipsilateral to i njection, SNAP elicited a bipolar metabolic pattern of low glucose met abolism proximal to the ventricle with higher values occurring more di stally. In control studies, we proved that the residue of SNAP decompo sition, N-acetylpenicillamine disulfide injected intraventricularly (2 mu mol), was without physiological, behavioral, or histological effec ts. Ventricular pretreatment with methylene blue (2 nmol), a putative inhibitor of guanylate cyclase and superoxide generator, suppressed se veral of the behavioral manifestations of 1 mu mol SNAP, such as the f orepaw 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), produce d fewer behavioral and cytotoxic effects over a 55-min observation per iod, but caused more intense and widely distributed metabolic stimulat ion, especially in commissural and projection white matter tracts. The results are the basis for a conscious rat model using intraventricula r injection of nitrocompounds to examine the physiological, behavioral , metabolic and cytotoxic properties of NO. in the brain.