Research Project
2026291
The neuropeptide, corticotropin releasing hormone (CRA), is the key coordinator of the neuroendocrine, behavioral and autonomic responses to stress. The principal investigator has shown that infusion of CRH into the cerebral ventricles of infant rats produces severe age- dependent limbic seizures. Multiple CRH-induced seizures result in selective neuronal death in amygdala and hippocampus. The seizures, like other CRH effects, are mediated via specific receptors. Two distinct members of the CRH-receptor family have been characterized CRF1 and CRF2. Both receptor types are found in amygdala, site of origin of CRH-induced seizures, and may therefore mediate this effect of CHR. The availability of ligands specific for one receptor type permits determination of the receptor mediating CRH-induced seizures. The goal of this collaborative proposal is to test the hypothesis that: 1) CRH induced seizures are mediated by CRF, and 2) that the seizures alter CRF1 (but not CRF2) gene expression. Selective non-peptide CRF1 antagonists will be administered by the P1 to infant rats prior to the infusion of CRH. Their ability to abolish the seizures induced by CRH will be compared to the established effects of non-selective peptide compounds, using both behavioral and EEG criteria. Brains of animals with CRH-induced seizures (and control brains) will be analyzed in the principal investigator's laboratory for messenger RNA levels of CRF1 and CRF2, using in situ hybridization, focusing on limbic regions. Authoradiographic studies will determine alterations in CRH-binding capacity of each receptor type in defined brain regions. This project builds on the strengths and expertise of the collaborators, it establishes CRH-induced seizures in infant rats as a reliable in vivo paradigm for testing candidate compounds as CRH receptor blockers. In essence, this Phase I project sets the stage for the commercial development of novel CRH receptor blockers as anti convulsants for selected seizure types.
