Previous work in our laboratory has established that corticotropin- releasing factor (CRF), when administered directly into the central nervous system, can have activating properties on behavior and can enhance behavioral responses to stress. CRF injected intraventricularly produces a dose-dependent increase in locomotor activity and increased responsiveness to an acoustic startle stimulus. However, this profile of activation changes to enhanced suppression of behavior in stressful situations and includes increased freezing, increased conditioned suppression, increased conflict, decreased feeding and decreased behavior in a novel open field. More recent work has established that these effects of CRF are independent of the pituitary adrenal axis and can be reversed by the CRF antagonist, alphahelical CRF. More importantly, the CRF antagonist can also reverse many behavioral responses to stressors. The purpose of the present proposal is to extend these observations by identifying the specific brain sites responsible for the response-activating the response-inhibiting actions of CRF. Preliminary results point to actions both at the nucleus locus coeruleus of the pons and in the amygdala of the forebrain. These two sites will be explored in detail using intracerebral injections of CRF on four simple but reliable dependent measures: locomotor activity, acoustic startle arousal response, decreased feeding, and response inhibition in an open field. The role of endogenous brain CRF systems in behavioral responses to stress will be explored using intracerebral injections of CRF antagonists with an emphasis on whether the role of CRF is stressor or response specific. In addition, the possibility that brain CRF has a role the exaggerated behavioral activation and the exaggerated behavioral response to stress associated with developmental and genetic factors will be explored by examining the ability of CRF antagonists to reverse the behavioral activation associated with neonatal and genetic manipulations. Finally, the role in behavioral responses to stress of the peptide, melanin concentrating hormone, and other peptides generated by the program project will be explored using these same behavioral paradigms. The results generated from these studies will be of significant importance for our understanding of the role of CRF in behavioral responses to stress and for our understanding how this system can be modified by developmental and/or genetic factors.
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