Stress is a factor in many psychopathological conditions, including depression, Post-Traumatic Stress Disorder and other anxiety disorders. Elucidating the reactivity and regulation of those brain systems responsible for modulating' the stress response is thus important for understanding the processes leading to such disorders, and possibly to developing novel or more effective treatment strategies- One such system is the brain noradrenergic system originating in the locus coeruleus (LC). Stress induces norepinephrine (NE) release in limbic regions such as the central amygdala (CeA) and bed nucleus of the stria terminalis (BSTL), enhancing behavioral activation and arousal. This system is also a target for antidepressant and mood-altering drugs used to treat stress-related disorders. However, while stress is a factor in many psychiatric disorders, not all individuals exposed to similar stress exhibit similar pathology. Thus, there is also a genetic component underlying a susceptibility to stress. This genetic predisposition, when combined with exposure to a sufficiently sensitizing environmental stimulus, results in stress-related psychopathology. In this project, we address these interacting genetic and environmental influences on the central noradrenergic system. Genetic predisposition will be studied by comparing rat strains differing in their reactivity and susceptibility to stress: Sprague-Dawley controls; Wistar-Kyoto (WKY) rats, which show behavioral inhibition to stress and increased susceptibility to stress pathology; and Lewis rats, which show blunted hormonal stress responses. We will investigate strain differences in reactivity of the brain NE system in response to acute immobilization stress, measured by changes in tyrosine hydroxylase (TH) mRNA in LC, and NE release in CeA and BSTL. We will compare endocrine and behavioral stress reactivity, measured by plasma ACTH and behavior on the social interaction and elevated plus maze tests. We will then compare the differential role played by NE in the CeA and BSTL of the three strains in modulating neuroendocrine and behavioral stress reactivity. In subsequent aims, we will investigate strain differences in the sensitizing effects of repeated cold stress exposure on noradrenergic, neuroendocrine and behavioral stress reactivity. Finally, we will determine how sensitization by repeated exposure to cold stress may alter the modulatory influence of NE in CeA and BSTL, and how this adaptive change in NE function may differ between the strains. Our hypothesis is that the behavioral inhibition shown by WKY rats results from reduced noradrenergic reactivity to stress, and that this may contribute to their stress susceptibility. We also hypothesize that cold sensitization will exacerbate the strain differences in noradrenergic reactivity that contribute to differences in behavioral and neuroendocrine reactivity. By comparing neurobiological differences between these strains, before and after sensitization, we hope to understand better the link between stress and disease states in vulnerable individuals
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