This application is the competitive renewal application of R01 MH 42088, seeking five years of support which would represent Years 12-16 of this project on the Psychobiology of Corticotropin-Releasing Factor. In the past eleven years, this grant has provided much evidence for a preeminent role for CRF-containing neurons in mediating the stress response, characterized in considerable detail the role for CRF as a neurotransmitter in the mammalian central nervous system (CNS), and perhaps most importantly contributed to the burgeoning data base which supports the hypothesis that CRF hypersecreted in patients with major depression. Contributions from this and several other laboratories, using a variety of multidisciplinary approaches in both preclinical and clinical settings have provided unequivocal evidence for hyperactivity of CRF-containing neurons in patients with major depression. The current proposal seeks to extend this work in directions largely based upon findings in the present funding period. Specifically, the investigator wishes to continue postmortem human brain tissue studies to further characterize the alterations in CRF-containing neurons and CRF receptor containing neurons by scrutinizing CRF and CRF receptor messenger ribonucleic acid (mRNA) expression, as well as focusing on the newly discovered CRF2 receptor and its endogenous ligand, urocortin. The investigator also intends to follow-up on his observations that establish CRF as the major mediator of the long-term effects of early untoward life events, proposing both preclinical and clinical studies. The former use the investigator's well established maternal deprivation model; the latter, utilizing the investigator's NIH funded General Clinical Research Center at Emory University Hospital, will seek to determine whether patients with major depression and a history of child abuse and/or neglect exhibit dramatic increases in CRF secretion. In addition, the investigator shall determine whether acute or chronic treatment with CRF1 receptor antagonists (CP-154526 and NBI-27914), novel antidepressant candidates, produce alterations in CRF and CRF receptor mRNA expression and hypothalamic-pituitary-adrenal (HPA) axis activity and whether such compounds exert activity as antidepressants in a validated animal model of depression. Finally, the effect of CRF on locus coeruleus (LC) norepinephrine (NE) neurons will be assessed in adult rats that had undergone maternal deprivation as neonates. These studies will furnish novel information on the role of CRF-containing neural systems in both the stress and response and in the pathophysiology of depression.
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