RFA-AA-17-016 states that ?Studies examining alcohol related behaviors in current models of PTSD and potentially in novel animal models of PTSD are sought?. Animal models of PTSD are on the cutting edge of exploiting individual differences to understand mechanisms underlying resilience and susceptibility to psychopathology. Validated models of PTSD recapitulate the prevalence of PTSD in trauma-exposed individuals (~15-30% depending on trauma). We will use 2 well-validated animal models of PTSD, social defeat stress and predator stress, to understand in what biological contexts trauma and subsequent enduring stress response provokes drinking behavior. Predator stress models the enduring effects of a severe single traumatic event while social defeat stress models effects of chronic physical and emotional stress. Both models produce variance in enduring response rates to trauma exposure, (30-50% of animals exhibit prolonged behavioral and neurobiological change), providing etiological validity for PTSD. We propose to examine if two highly translatable markers of trauma-symptom development, sleep disturbance and increased peripheral immune signaling, predict development and/or maintenance of drinking after stress in rodents. This approach addresses the RFA mandate to ?identify biomarkers that will predict transition of PTSD to comorbid PTSD-alcohol misuse.? The goal is to (1) develop robust cross-species biomarkers of long term-trauma effects associated with increased alcohol consumption and (2) identify biomarkers that are predictive for treatment response. We will test the hypothesis that sleep and inflammation abnormalities after trauma predict increased drinking and treatment response. To test this hypothesis we will use a large (N=200/model) prospective, longitudinal design based on clinical research approaches. This strategy enables use of sophisticated statistical models to identify biological predictors of drinking behavior. We will assess clinical relevance by comparing these findings to humans by leveraging our clinical database of a prospective, longitudinal study of trauma in active duty service members (N=2600). This database includes data on trauma, PTSD symptoms, alcohol dependence, sleep and peripheral inflammation both before and after a combat deployment. Once validated, sleep and immune biomarkers identified in our animal models and validated in humans can be used to screen for prophylactic and therapeutic treatment effects of novel pharmacotherapies.
This project aims to develop rodent models of trauma-induced alcohol drinking using a clinical study based design for identification of new treatment targets for comorbid post-traumatic stress disorder (PTSD) and alcohol use disorder. Single and repeated trauma effects on sleep and blood-based inflammatory markers will be examined to identify translational biomarkers that predict development of alcohol use after trauma. Markers that predict development of drinking in rodents will be verified for predictive utility in humans using previously collected data on sleep, inflammation and alcohol use in a longitudinal study of PTSD.
|Der-Avakian, Andre; Pizzagalli, Diego A (2018) Translational Assessments of Reward and Anhedonia: A Tribute to Athina Markou. Biol Psychiatry 83:932-939|
|Deslauriers, Jessica; Toth, Mate; Der-Avakian, Andre et al. (2018) Current Status of Animal Models of Posttraumatic Stress Disorder: Behavioral and Biological Phenotypes, and Future Challenges in Improving Translation. Biol Psychiatry 83:895-907|