THE EFFECT OF ASTRESSIN, A NOVEL ANTAGONIST OF CORTICOTROPIN-RELEASING HORMONE (CRH), ON CRH-INDUCED SEIZURES IN THE INFANT RAT - COMPARISON WITH 2 OTHER ANTAGONISTS

Corticotropin releasing hormone (CRH) has both neuroendocrine effects, promoting ACTH release from the anterior pituitary, and neurotransmit ter properties, acting on specific neuronal populations, A recently de signed CRH analogue has been shown to be highly potent in preventing a ctivation of pituitary CRH receptors, The efficacy of this compound, ' Astressin', in blocking the effects of CRH in the central nervous syst em (CNS) has not been determined, CRH induces prolonged amygdala-origi n seizures in neonatal and infant rats, This model was used in the cur rent study, to compare Astressin to alpha-helical CRH-(9-41), and to [ D-Phe(12), Nle(21,38), C-MeLeu(37)]CRH-(12-41), ie D-Phe-CRH-(12-41). Astressin (3 or 10 mu g) was infused into the cerebral ventricles of i nfant rats prior to CRH infusion, Both doses of the analogue significa ntly delayed the onset of CRH-induced seizures when given 15, but not 30 min before CRH, No effect of the lower Astressin dose on seizure du ration was demonstrated; the higher dose prevented seizures in 2/12 ra ts, and delayed seizure onset in the others (22.7+/-5 min vs 10.1 +/- 1.3 min), In the same paradigm, 10 mu g of alpha-helical CRH-(9-41) an d 5 mu g of D-Phe-CRH-(12-41) had comparable effects on seizure latenc y and duration. Electroencephalograms confirmed the behavioral effects of Astressin, Therefore, in a CNS model of CRH-mediated neurotransmis sion, the potency of Astressin is not substantially higher than that o f alpha-helical CRH (9-41) and D-Phe-CRH-(12-41).