METABOLIC AND NEUROANATOMICAL CORRELATES OF BARREL-ROLLING AND OCULOCLONIC CONVULSIONS INDUCED BY INTRAVENTRICULAR ENDOTHELIN-1 - A NOVEL PEPTIDERGIC SIGNALING MECHANISM IN VISUOVESTIBULAR AND OCULOMOTOR REGULATION

The neuroactive peptide endothelin-1 has receptors distributed abundan tly among subdivisions and nuclei of the visuovestibular and oculomoto r systems. In previous work, we and others described the convulsive ma nifestations resulting from central injection of this neuropeptide, in cluding nystagmus, oculoclonus, exophthalmos, tonic hindlimb extension , and a generalized repetitive motor disturbance called barrel-rolling . We applied the quantitative, autoradiographic [C-14]deoxyglucose met hod to examine the hypothesis that visuovestibular and oculomotor stru ctures would become metabolically stimulated when endothelin was intro duced into the brain via the ventricular system in conscious rats. Sin ce previous work had demonstrated that hypermetabolic responses to end othelin in other neural systems were inhibited by an antagonist of neu ronal calcium L-type channels, nimodipine, we further tested whether t he increased function of vestibulooculomotor nuclei whose metabolic ac tivity was sensitive to endothelin could be altered following nimodipi ne pretreatment via the ventricle. A single unilateral injection of en dothelin (9 pmol in 3 mul saline) into a lateral ventricle provoked si gnificantly increased rates of glucose metabolism in 22 of 39 individu al anatomical structures of the visuovestibular and oculomotor systems . Among those affected were the superficial stratum of the caudal supe rior colliculus (+25%), the optic tract bilaterally (+35 to 43%), the oculomotor cranial nerve nuclei (III, IV, VI; range of +21 to 47%), an d the medial terminal nucleus of the accessory optic tract which harbo rs dense fields of endothelin binding sites (bilateral increase of +70 to 96%). Several other nuclei involved in the proprioceptive and visu ovestibular disturbance caused by endothelin displayed increased metab olic activity, including the cuneate, gracile, sensory trigeminal, and prepositus hypoglossal nuclei, the vestibular subnuclear system, and the cerebellar flocculus. Identification of hypermetabolic responsivit y to endothelin in these structures provides further information on th e anatomical substrates mediating the behavioral phenomenology of endo thelin-induced motor convulsions which involve the paroxysmal particip ation of the extraocular muscles and motor control systems producing b arrel-rolling convulsions. Nimodipine pretreatment inhibited both the convulsive activity and the cerebral hypermetabolic responses to intra ventricular endothelin. The results indicate that the neural systems s ensitive to intraventricular endothelin become functionally active via a calcium-mediated process that may involve the neuropeptide as an in trinsic signaling molecule.