Role of Neuropeptides in Stress-Induced Escalation of Alcohol Drinking

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Traumatic stress disorders affect millions of Americans and cost the U.S. billions of dollars annually. Alcohol use disorder (AUD) affects ~12% of the world population, contributing to >2.5 million deaths per year in the U.S. and costing the U.S. $220 billion annually. Post-traumatic stress disorder (PTSD) triples the risk for developing AUD. PTSD and AUD increase mortality in humans by increasing the incidence of chronic disease. PTSD diagnoses are also associated with higher incidence of chronic pain in humans. Current treatment strategies for PTSD, AUD and chronic pain are sub-optimal. The goal of the proposed work is to 1) test traumatic stress effects on the activity of molecularly identified neurons in central amygdala (CeA) that project to reward/aversion and pain centers and 2) test the role of specific CeA projection cells in mediating stress effects on alcohol reward/aversion and sensory nociception & pain avoidance. We will use an established animal model of traumatic stress in which rats are exposed to predator odor (i.e., bobcat urine), then indexed for avoidance of the odor-paired context; this model is predicated on the fact that avoidance is a hallmark symptom of PTSD in humans. Similar to what is seen in humans with traumatic stress disorders, our published data show that Avoiders exhibit escalation of alcohol drinking and hyperalgesia after stress. We will use this model to test circuit and molecular mechanisms mediating traumatic stress effects on behavior. Specific Aim 1 tests the prediction that traumatic stress activates LH-projecting CeA CRFR1+ cells and inhibits vlPAG-projecting CeA CRFR1+ cells in alcohol-drinking male and female CRFR1:cre rats. Specific Aim 2 tests the prediction that inhibition of LH-projecting CeA CRFR1+ cells will reverse stress-induced increases in alcohol self-administration and reductions in alcohol aversion in male and female CRFR1:cre rats. Specific Aim 3 tests the prediction that activation of vlPAG-projecting CeA CRFR1+ cells will reverse stress-induced hyperalgesia and increases in pain avoidance in male and female CRFR1:cre rats. We will use brain slice electrophysiology, anatomical tract-tracing, retrograde neural labeling and molecular biology techniques, combined with circuit-based and pharmacological approaches to test stress effects on behavior in CRFR1:cre rats developed by our lab.