The role of mGlu receptors in susceptibility to stress-induced anhedonia, fear, and anxiety-like behavior.

Stress and trauma exposure contribute to the development of psychiatric disorders such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) in a subset of people. A large body of preclinical work has found that the metabotropic glutamate (mGlu) family of G protein-coupled receptors regulate several behaviors that are part of the symptom clusters for both PTSD and MDD, including anhedonia, anxiety, and fear. Here, we review this literature, beginning with a summary of the wide variety of preclinical models used to assess these behaviors. We then summarize the involvement of Group I and II mGlu receptors in these behaviors. Bringing together this extensive literature reveals that mGlu5 signaling plays distinct roles in anhedonia, fear, and anxiety-like behavior. mGlu5 promotes susceptibility to stress-induced anhedonia and resilience to stress-induced anxiety-like behavior, while serving a fundamental role in the learning underlying fear conditioning. The medial prefrontal cortex, basolateral amygdala, nucleus accumbens, and ventral hippocampus are key regions where mGlu5, mGlu2, and mGlu3 regulate these behaviors. There is strong support that stress-induced anhedonia arises from decreased glutamate release and post-synaptic mGlu5 signaling. Conversely, decreasing mGlu5 signaling increases resilience to stress-induced anxiety-like behavior. Consistent with opposing roles for mGlu5 and mGlu2/3 in anhedonia, evidence suggests that increased glutamate transmission may be therapeutic for the extinction of fear learning. Thus, a large body of literature supports the targeting of pre- and post-synaptic glutamate signaling to ameliorate post-stress anhedonia, fear, and anxiety-like behavior.