Metabotropic glutamate receptor 5 in the nucleus accumbens promotes resilience in various animal models of stress : in vivo assessment adopting knockout mice and viral mediated gene transfer

Abstract

Although there is a substantial causal relationship between the occurrence of stressful life events and the subsequent onset of depression, stress per se is not sufficient to the development of depression. Resilience, the ability to avoid deleterious behavioral changes in response to extreme stress, plays a central role in determining 2 whether stress can cause depression. Metabotropic glutamate receptor 5 (mGluR5) has been suggested as a potential pharmacologic target for the depression. However, the possible role of mGluR5 activity in mediating resilience to stress has not been explored. In this study, I found that mGluR5-/- mice exhibited increased behavioral vulnerability to stress, including enhanced helplessness, social withdrawal, and decreased sucrose preference after various stressful events. Lentiviral rescue of mGluR5 in the nucleus accumbens shell reversed the stress-induced depressive-like behaviors of mGluR5-/- mice. Furthermore, induction of ∆FosB in the nucleus accumbens upon stress, an important molecular event for promoting resilience, was impaired in mGluR5-/- mice. Notably, targeted activation of mGluR5 in the nucleus accumbens shell increased the expression of ∆FosB. Taken together, these results demonstrate that mGluR5 is an essential molecule for promoting resilience to stress and defects in mGluR5 signaling in the nucleus accumbens may be a predisposition that interacts with stress to increase vulnerability for depression.