CORTICOTROPIN-RELEASING FACTOR IN HORMONAL AND BEHAVIORAL RESPONSES TO STRESS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To characterize the corticotropin-releasing factor system in the brain and pituitary of the marmoset and evaluate its role in endocrine and behavioral responses to stress. Corticotropin-releasing factor (CRF) is a neuropeptide that regulates the behavioral, hormonal, autonomic, and immune responses to stress and may contribute to the pathophysiology of mood and anxiety disorders in humans. To develop a nonhuman primate model of the endocrine and behavioral effects of CRF hypersecretion, we performed pilot tests characterizing the expression of CRF type-1 (CRFR1) and type-2 (CRFR2) receptors and CRF-binding protein (CRF-BP) in the marmoset pituitary, and assessing the effects of antalarmin, a selective CRFR1 antagonist, on hormonal and behavioral responses to CRF and stress. The sequences for the cloned regions of the marmoset CRFR1, CRFR2, and CRF-BP were found to be 98% homologous with the human genes at the DNA level, and for CRFR1 and CRFR2, 100% identity for the predicted protein sequence of the amplified region. The cloned region of the marmoset CRF-BP was found to be 96% homologous to human at the nucleic acid level and 98% identity at the predicted protein level. We observed that the CRFR1 and CRFR2 mRNAs were of nearly equal abundance in the marmoset pituitary, providing for potential regulation of adrenocorticotropin (ACTH) production and secretion by both of these CRF receptors in this species. Antalarmin reduced the ACTH response to ovine CRF as well as the ACTH and cortisol responses to a restraint stressor, but did not alter basal plasma ACTH or cortisol concentrations. These studies indicate that CRF acts on CRFR1 to stimulate ACTH release in the marmoset, but suggest that CRF acting through CRFR2, and/or other secretagogues, may also play a significant role in regulating ACTH release under baseline conditions. These findings will for a crucial basis for further studies of the role of CRF on responses to stress in the marmoset. This research used the WNPRC marmoset colony, Assay Services and Pathology Services.