The Effect of Ventral Tegmental Area Rictor Knockout on Susceptibility to Chronic Social Defeat Stress and Stress‐induced Changes in Morphine Reward

Abstract

There is significant co‐morbidity of addiction and depression and this may be due to dysregulation of common brain circuits. For example, similar alterations in signaling in the ventral tegmental area (VTA) have been identified in response to both chronic morphine and chronic social defeat stress (CSDS), a rodent model of depression. We are particularly interested in target of rapamycin complex 2 (TORC2) signaling in the VTA as it has been established to play a critical role in morphine reward and morphine‐induced neuroadaptations. However, whether it plays a similar role in stress‐induced changes in morphine reward, or stress susceptibility itself, is unknown. To address these questions, we used viral and genetic approaches to decrease VTA TORC2 signaling by knocking out the expression of Rictor, a TORC2 component protein necessary for TORC2 function. Floxed‐Rictor mice were either crossed with a TH‐Cre mouse line to eliminate TORC2 signaling in all catecholaminergic neurons or underwent stereotaxic surgery to specifically decrease TORC2 signaling in the VTA via AAV‐Cre infusion. The mice were then subjected to chronic physical or emotional CSDS and their susceptibility to stress was measured using the social interaction (SI) test. Following SI testing, mice underwent a two‐bottle choice assay to assess voluntary morphine preference and consumption. In contrast to previous data that found that decreasing AKT signaling was sufficient to increase susceptibility to stress, we found that decreased VTA TORC2 signaling did not alter stress susceptibility. However, we did observe a difference in morphine consumption, as Rictor knockout mice (both TH‐Cre positive and AAV‐Cre) that underwent stress consumed significantly more morphine than stressed controls (intact TORC2 signaling). Additionally, following stress, Rictor knock‐out mice also exhibited an increase in water and sucrose consumption, suggestive of an overall increase in consummative drive. Importantly, these changes were only evident in mice following stress, suggesting a novel role for VTA TORC2 signaling in stress‐mediated changes in consumption.Support or Funding InformationThis work was supported by NIH T32 GM092715 (SK) and NIDA DA037426 (MMR).