Prefrontal Cortex Stress Peptides in Traumatic Stress-Induced Escalation of Alcohol Drinking

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 DESCRIPTION (provided by applicant): Alcohol use disorder (AUD) affects ~12% of the world population, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $220 billion annually. Traumatic stress disorders (e.g., post-traumatic stress disorder; PTSD) are debilitating disorders currently affecting 7.7 million Americans, are observed in ~30% of U.S. combat veterans, and cost the U.S. billions of dollars annually. AUD and PTSD both increase mortality rates and shorten life spans in humans, increasing the incidence of chronic disease states. AUD is the most commonly occurring mental health disorder in humans affected by PTSD, with 22-43% of individuals with PTSD meeting criteria for AUD (compared to 8% of the general population). The high rate of co-morbidity suggests an overlapping neurobiological mechanism between PTSD and AUD, but the biological basis for the high rate of co-morbidity between PTSD and AUD is not known. An important aspect of this proposal is the a priori identification of individual differences in stres reactivity (vulnerability vs. resilience), which models the development of traumatic stress disorders in only a subpopulation of stress- exposed humans. Here, we propose to use a rodent model to examine the neurobiological basis for co-morbid PTSD and AUD. Preliminary and published data from our lab suggest that traumatic stress escalates alcohol drinking and produces hyperalgesia in rats via effects on corticotropin-releasing factor (CRF; a pro-stress peptide) signaling, and also alters extracellular signal-related kinase phosphorylation (pERK) in the ventromedial prefrontal cortex (vmPFC), a brain region important for coordinating responses to the environment via top-down control of sub-cortical structures. The proposed work seeks to extend these findings by exploring the role of CRF-ERK interactions in the vmPFC in mediating traumatic stress-induced escalation of alcohol drinking and hyperalgesia. The overarching hypothesis of this proposal is that vmPFC CRF-CRF1R signaling via ERK pathways mediates escalated alcohol drinking and hyperalgesia in rats that exhibit high stress reactivity. This proposal will provide a promising M.D./Ph.D. student with vital research training through studies that use an integrative approach to test the predictions that: 1) traumatic stress upregulates CRF- CRF1-ERK signaling pathways in the vmPFC, and 2) this pathway mediates escalation of alcohol drinking in high-stress reactive animals. These experiments will train a future physician-scientist in animal models of psychiatric disorders, and the results of these studies will inform the development of effective treatment strategies for co-morbid PTSD and AUD, leading to improvements in quality of life and health of affected individuals, decreasing morbidity associated with these disorders, and potentially saving the U.S. millions of dollars in health care costs.