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), into a lateral ventricle (ICV) of rats produced barrel rolling and other 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 hypermetabolic correlates of the convulsive activity in numerous brain regions. The present study tested whether the effects of ET were dose dependent by assessing 13 behavioral, 9 physiological, and brain metabolic responses in six individual structures of rats treated separately with ICV ET in doses between 1.5 and 18 pmol. Barrel-rolling convulsions, having a threshold for onset at 3 pmol, displayed increased incidence and severity, and a shorter latency to onset, with the higher ET doses. Within 10-20 min, ET evoked dose-dependent increases in mean arterial pressure and plasma glucose levels, and a significant reduction in arterial PCO2. Among brain structures, the periventricular caudate nucleus near the injection site had an elevated rate of glucose metabolism (+60%) at a 3 pmol threshold. The substantia nigra pars reticulata, medial terminal nucleus of the accessory optic tract, rostral lamella of the inferior olivary nucleus, cerebellar paramedian lobule, and cerebellar copula pyramis, ah of which have moderate to dense populations of ET-1 receptors and are related by anatomical connections, displayed significant metabolic stimulation by 9 pmol ET (+47 to +122%). The behavioral, physiological, and focal hypermetabolic effects of the central ET appear to be time coordinated, interrelated, and dose dependent. Identification of the threshold dose for central actions of ET at 3 pmol ICV reveals this peptide as the most potent neuroactive substance yet described in vivo.