A Novel Emotional Stress Model of Co-morbid Opiate Use and Mood Disorders

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DESCRIPTION (provided by applicant): Co-morbidity of opiate use and mood disorders such as depression and post-traumatic stress is a significant health and financial burden, one that will likely increase given the increase in both abuse and prescription of pain-relieving opiate drugs in the US. Most preclinical models of mood disorders, such as chronic social defeat stress, involve a physical trauma, thus complicating the study of pain-relieving opiate drugs. It is critical to develop a preclinical model that lacks the confound of physical pain to evaluate the molecular mechanisms that underlie opiate abuse and the impact of stress on initiating or exacerbating use. This proposal aims to use the recently developed emotional stress model to address the central hypothesis that exposure to chronic psychological stress impacts morphine reward and consumption and can serve as a mouse model of co-morbid opiate dependence and mood disorders. The chronic social defeat stress model has strong face validity for post- traumatic stress disorder and depression and a dependence on altered ventral tegmental area dopamine neuron activity. A modified version of this protocol lacking physical pain called chronic emotional stress, in which mice witness but are not physically exposed to social defeat stress, will be used to evaluate the effect of emotional stress on morphine reward and consumption. Specific Aim 1 will determine whether exposure to physical or emotional social defeat stress alters morphine reward using conditioned place preference. Specific Aim 2 will evaluate whether chronic physical or emotional stress alters the voluntary intake of morphine using a two-bottle preference paradigm that takes advantage of the C57BL/6J strain's propensity to consuming oral morphine. Specific Aim 3 will determine whether mice exposed to chronic emotional stress alter their drinking during the stress experience, and what effect consumption of morphine during stress has on the expression of stress-induced behavioral changes such as social avoidance. Preliminary data are presented that show susceptibility to physical social defeat stress increases morphine reward and that there is a negative correlation between social interaction score and morphine preference, indicative of depressive-like behavior increasing morphine reward. It is expected that emotional stress will produce a similar effect, with mice susceptible to emotional stress showing an increase in preference for morphine. Data are also presented that following chronic physical and emotional stress voluntary morphine consumption is increased and that consumption is negatively correlated with social interaction. It is expected that mice will also increase morphine consumption during emotional stress, exacerbating stress-induced behavioral changes such as social avoidance. Completion of the proposed work will provide a novel model of co-morbid mood disorders and opiate use that can be utilized in future studies to examine the molecular mechanisms that underlie behavioral changes induced by opiate drugs or stress, a necessary step in the development of novel therapeutic options.