DOSE-RELATED POTENT BRAIN-STIMULATION BY THE NEUROPEPTIDE ENDOTHELIN-1 AFTER INTRAVENTRICULAR ADMINISTRATION IN CONSCIOUS RATS

Injection of the neuropeptide, endothelin-1 (ET, range of 3-9 pmol), i nto a lateral ventricle (ICV) of rats produced barrel rolling and othe r convulsions including ataxia, forelimb and facial clonus, nystagmus, and tonic extension of the tail and hindlimbs. Using the quantitative autoradiographic [C-14]deoxyglucose method, we resolved the focal hyp ermetabolic correlates of the convulsive activity in numerous brain re gions. The present study tested whether the effects of ET were dose de pendent by assessing 13 behavioral, 9 physiological, and brain metabol ic responses in six individual structures of rats treated separately w ith ICV ET in doses between 1.5 and 18 pmol. Barrel-rolling convulsion s, having a threshold for onset at 3 pmol, displayed increased inciden ce and severity, and a shorter latency to onset, with the higher ET do ses. Within 10-20 min, ET evoked dose-dependent increases in mean arte rial pressure and plasma glucose levels, and a significant reduction i n arterial PCO2. Among brain structures, the periventricular caudate n ucleus near the injection site had an elevated rate of glucose metabol ism (+60%) at a 3 pmol threshold. The substantia nigra pars reticulata , medial terminal nucleus of the accessory optic tract, rostral lamell a of the inferior olivary nucleus, cerebellar paramedian lobule, and c erebellar copula pyramis, ah of which have moderate to dense populatio ns of ET-1 receptors and are related by anatomical connections, displa yed significant metabolic stimulation by 9 pmol ET (+47 to +122%). The behavioral, physiological, and focal hypermetabolic effects of the ce ntral ET appear to be time coordinated, interrelated, and dose depende nt. Identification of the threshold dose for central actions of ET at 3 pmol ICV reveals this peptide as the most potent neuroactive substan ce yet described in vivo.