We propose to more completely characterize the effects of corticotropin releasing hormone (CRH) administered intracerebroventricularly (ICV) to nonhuman primates and to determine whether endogenous CRH brain systems are involved in the primate's response to a stressor. Investigators have hypothesized that CRH systems play an integrative role in organizing the physiological and behavioral responses to a stressor. Previous work on the relationship between CRH and the stress response has primarily employed rodent models. Significant neurobiological differences exist between primates and rodents. In preliminary experiments, we found that CRH affects neuroendocrine systems, autonomic functioning, and behavior when administered centrally to rhesus monkeys; and while some differences were noted, our data were generally consistent with studies performed in rodents. Additional data are needed to define what role brain CRH plays in the response to a stressor. The use of monkeys in our studies will provide the basis for an animal model relevant to humans that will allow further exploration of the role that central CRH plays in regulating and integrating the human stress response. A comparison of rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) monkeys will establish the effects of CRH in two closely related species whose innate behavioral dispositions are, nevertheless, different. In the proposed studies, we will extend our previous work by more completely characterizing the effects of centrally administered CRH in a larger group of monkeys. Complete dose-response studies with CRH and the CRH antagonist (CRHa) will be performed, as will studies to establish the degree to which the CRH-induced effects are specific to this peptide. In Part 1, we will establish the degree to which CRH's effects are modulated by (i) species differences in behavioral disposition, (ii) sex of the animal, (iii) time of day of administration, and (iv) brain site of administration. The experiments in Part 2 will be based on data from these studies. In Part 2, CRH and CRHa will be administered to monkeys already exhibiting varying levels of behavioral and endocrine arousal. Based on the hypothesis that endogenous brain CRH systems play a role in mediating the stress response, we predict that exogenously administered CRH will enhance and CRHa will diminish the ongoing level of arousal.
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