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.
The proposed studies will investigate the role of mammalian target of rapamycin complex 2 signaling in dopamine neurons in the ventral tegmental area in mediating stress-induced changes in morphine reward and consumption. These studies utilize chronic emotional stress, a novel preclinical mood disorder model that eliminates the confound of physical pain, a critical barrier to the study of pain-relieving opiate drugs and identificationof neurobiological mechanisms that could potentially yield novel therapeutic targets. Comorbidity of drug dependence and mood disorders is a significant burden to public health and this work addresses NIDA's high priority interests in research aimed at understanding the comorbidity of addiction and mental disorders and in developing novel interventions for opiate addiction.
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