A NEW EXPERIMENTAL-MODEL OF EPILEPSY BASED ON THE INTRAVENTRICULAR-INJECTION OF ENDOTHELIN

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventr icle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [C-14]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET -1-induced convulsions in rats are high rates of glucose utilization b y structures near the site of LCV injection and throughout a diverse c ircuit of anatomically related brain regions. We speculate that this c ircuitry connects the caudate nucleus (putative site of initial stimul ation in the forebrain) to the paramedian lobule and vermis of the cau dal cerebellar cortex in the hindbrain. We evaluated the behavioral, p hysiological, and hypermetabolic responses to central ET-1 in the pres ence of three agents with anticonvulsant properties, providing clues a bout the cellular mechanisms of this convulsive and hypermetabolic sta te. Intraventricular MK-801 [a noncompetitive antagonist of glutamic a cid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or me thylene blue (an inhibitor of guanylate cyclase, the enzyme on which n itric oxide acts) each produced significant attenuation of the behavio ral and cerebral metabolic activation. The results introduce several q uantitative parameters for an experimental model of employing intraven tricular ET-1 in rats to study mechanisms of peptidergic convulsive di sorders and the efficacies of promising anticonvulsant compounds in th e treatment of epilepsy.