Neurobiology of Stress Inoculation

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DESCRIPTION (provided by applicant): The negative consequences of stress are well-recognized in mental health research. Interestingly, however, prior stress exposure has also been linked to the subsequent development of resilience. Variously described as inoculating, immunizing, steeling, toughening, or thriving, the notion that prior stress exposure facilitates the development of subsequent resilience is tested in the proposed research using alprazolam to diminish key aspects of stress inoculation that are thought to foster resilience. Alprazolam is a benzodiazepine medication that reduces acute anxiety and attenuates hypothalamic-pituitary-adrenal (HPA) axis activation by stress. In animal models, benzodiazepines also interfere with learned extinction of conditioned fear. Conversely, the anxiogenic compound yohimbine activates the HPA axis and accelerates learned extinction of conditioned fear. These findings are consistent with evidence that cognitive and emotional processing of acute anxiety and HPA axis activation promote recovery from stress-related psychiatric disorders. The proposed research tests the hypothesis that acute anxiety and HPA axis activation facilitate the development of stress inoculation-induced resilience. Animals randomized to receive alprazolam or the vehicle control before each weekly stress inoculation training session are compared to non-inoculated animals administered alprazolam or vehicle and assessed at later ages on established behavioral and neuroendocrine measures of resilience. If cognitive and emotional processing of acute anxiety and HPA axis activation are necessary for the development of stress inoculation-induced resilience, then animals administered alprazolam before stress inoculation training sessions will subsequently resemble animals from both non-inoculated treatment conditions with diminished indications of resilience compared to the stress inoculated vehicle treatment condition. This research will extend our understanding of the capacity for enhancing mental health, with the goal of advancing preventative strategies designed to most efficiently foster the development of resilience. Results from these studies will also provide insights on whether benzodiazepines aid or interfere with behavioral therapies, and will help to clarify the role of re-experiencing stressors during therapeutic interventions. These issues are important because of concerns that re-experiencing stressors may exacerbate psychiatric symptoms and impede recovery instead of fostering the development of resilience.