Michelle Mazei-Robison, Ph.D. - US grants

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.

? DESCRIPTION (provided by applicant): Despite the widespread use of opiate drugs, neuroadaptations that underlie opiate abuse remain obscure, limiting treatment. Treatment is further complicated by the presence of comorbid mood disorders, with little known about the molecular mechanisms contributing to comorbidity. This knowledge gap is problematic, as rodent models of mood disorders often employ physical stressors that confound study of pain-relieving opiate drugs. This proposal aims to use chronic emotional stress, a novel variant of the chronic social defeat stress model, to eliminate physical trauma in order to investigate the role of mammalian target of rapamycin complex 2 (TORC2) signaling in stress-induced changes in opiate reward and consumption. TORC2 is a critical mediator of morphine-induced changes in ventral tegmental area (VTA) dopamine (DA) neuron activity and morphology that alter reward behavior, and is also favorably positioned to mediate stress-induced changes in reward. This proposal will address the central hypothesis that VTA TORC2 signaling controls stress-induced changes in morphine reward and consumption and alters VTA DA neuron structure by completing the following Aims, which utilize behavioral, biochemical, and morphological approaches. Specific Aim 1 will provide a comprehensive, temporal determination of the effect of chronic emotional stress on morphine reward using conditioned place preference and voluntary two-bottle choice assays and VTA TORC2 signaling via western blot. Specific Aim 2 will determine whether VTA TORC2 signaling is necessary and sufficient for stress-induced changes in morphine reward by utilizing viral constructs that overexpress Rictor to increase VTA TORC2 signaling and floxed-Rictor mice to decrease DA cell TORC2 signaling. Specific Aim 3 will evaluate the effects of morphine and emotional stress on VTA DA neuron morphology, including the role of TORC2 signaling, by examination of VTA DA soma size and dendritic spine density. Preliminary data find that emotional stress bidirectionally alters morphine reward, decreasing intake during, and increasing intake following stress. Reward changes correlate with VTA TORC2 signaling, which is initially decreased, then increased post-stress. Novel data show that emotional stress induces a long-lasting increase in morphine reward, with a negative correlation between social interaction and morphine preference, indicating that depressive-like behavior increases morphine reward. Finally, data show that chronic stress decreases VTA DA soma size similarly to chronic morphine, a morphological change that is correlated with altered VTA DA neuronal activity and reward behavior, and has been previously shown to be mediated by decreased TORC2 signaling. Completion of these studies will establish bidirectional TORC2 signaling as a mediator of stress- induced changes in morphine reward and structural plasticity, identifying a novel signaling pathway and mechanistic approach for pharmacological treatment of opiate dependence and comorbid mood disorders.