THE CRF1 RECEPTOR MEDIATES THE EXCITATORY ACTIONS OF CORTICOTROPIN-RELEASING FACTOR (CRF) IN THE DEVELOPING RAT-BRAIN - IN-VIVO EVIDENCE USING A NOVEL, SELECTIVE, NONPEPTIDE CRF RECEPTOR ANTAGONIST

Corticotropin releasing factor (CRF) is the key coordinator of the neu roendocrine and behavioral responses to stress. In the central nervous system, CRF excites select neuronal populations, and infusion of CRF into the cerebral ventricles of infant rats produces severe age-depend ent limbic seizures. These seizures, like other CRF effects, result fr om activation of specific receptors. Both of the characterized members of the CRF receptor family (CRF1 and CRF2), are found in the amygdala , site of origin of CRF-induced seizures, and may therefore mediate th ese seizures. To determine which receptor is responsible for the excit atory effects of CRF on limbic neurons, a selective, non-peptide CRF1 antagonist was tested for its ability to abolish the seizures, in comp arison to non-selective inhibitory analogues of CRF. Pretreatment with the selective CRF1 blocker (NBI 27914) increased the latency and decr eased the duration of CRF-induced seizures in a dose-dependent manner. The higher doses of NBI 27914 blocked the behavioral seizures and pre vented epileptic discharges in concurrent electroencephalograms record ed from the amygdala. The selective CRF1 blocker was poorly effective when given systemically, consistent with limited blood-brain barrier p enetration. Urocortin, a novel peptide activating both types of CRF re ceptors in vitro, but with preferential affinity for CRF2 receptors in vivo, produced seizures with a lower potency than CRF. These limbic s eizures, indistinguishable from those induced by CRF, were abolished b y pretreatment with NBI 27914, consistent with their dependence on CRF 1 activation. In summary, CRF induces limbic seizures in the immature rat, which are abolished by selective blocking of the CRF1 receptor. C RF1-messenger RNA levels are maximal in sites of seizure origin and pr opagation during the age when CRF is most potent as a convulsant. Take n together, these facts strongly support the role of the developmental ly regulated CRF1 receptor in mediating the convulsant effects of CRF in the developing brain. (C) 1997 Elsevier Science B.V.