Exposure to stressors is nearly inevitable over the course of the human lifespan. Exposure to a severe stressor, or trauma, is also prevalent, with estimates of lifetime exposure to trauma ranging from 54% to 89% depending on the geographical region assessed (Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Mylle & Maes, 2004). A subpopulation of trauma-exposed individuals later develops Post-traumatic Stress Disorder (PTSD). PTSD is a multidimensional anxiety disorder. DSM-5 criteria for PTSD diagnosis include the presence of symptoms in each three categories (intrusion of trauma-related images and memories, avoidance of trauma-related stimuli, and negative alterations in cognition and/or mood) that last for more than a month after the trauma and have a negative impact on the quality of life (American Psychological Association, 2013). Symptoms of increased arousal (e.g., heightened startle response, hypervigilance) may also be present but are not required for diagnosis. Symptoms in the “negative alterations in cognition and/or mood” category of PTSD diagnostic criteria overlap with those for Major Depressive Disorder, which is also exacerbated by stress, including: loss of interest or pleasure in daily activities, anhedonia, negative affect, insomnia, and guilt (American Psychological Association, 2013).

The neurobiology underlying susceptibility to stress-induced disorders is complex and involves many hormone and neurotransmitter systems. The metabotropic glutamate receptors (mGlu's) have been implicated in fear, anxiety, anhedonia and susceptibility to the development of PTSD and as such, are the focus of the present review. mGlu receptors are G protein-coupled receptors (GPCRs). There are three families, or “groups” of mGlu receptors: Group I, II, and III. These groups are defined based on their G-protein coupling and signaling as well as amino acid sequences (4). Group I mGlu receptors include mGlu1 and mGlu5 receptors, group II includes mGlu2 and mGlu3 receptors, and group III includes mGlu4, mGlu6, mGlu7, and mGlu8 receptors. Group I mGlu receptors are coupled to Gq/11 proteins and group II and III receptors are coupled to Gi/o proteins (Niswender & Conn, 2010). With the exception of mGlu6, which is expressed in the retina, mGlu receptors are found at moderate-to-high levels of expression throughout the CNS, primarily in neurons. mGlu5 is also expressed in astrocytes. However, the synaptic localization differs by group, with Group I mGlu's predominantly expressed post-synaptically. Group II and III mGlu's are expressed post-synaptically as well, but are primarily expressed pre-synaptically where they can serve as autoreceptors to reduce glutamate release. See (Niswender & Conn, 2010) for a thorough review of mGlu expression and pharmacology.

Studies using genetic or pharmacological manipulation of mGlu function have found roles for these receptors in fear, anxiety, and anhedonia. The majority of this research focuses on three mGlu receptors: the Group II receptors (mGlu2 and mGlu3) and the Group I receptor (mGlu5). Here, we will review the preclinical literature investigating the role of these receptors in mediating fear, anxiety and anhedonia arising from exposure to a stressor, with a focus on their role in susceptibility and resilience to the long-term consequences of stress. First, we will summarize the rodent models used to induce stress and to assess anhedonia, fear, and anxiety-like behavior in studies that assess the involvement of mGlu receptors. This will be followed by a summary of the results of studies assessing the role of mGlu2, mGlu3, and mGlu5 in such behaviors. For the most part, we will not discuss studies which assessed these behaviors in the absence of a stressor, unless necessary to clarify results. Unless noted, all studies were done using male rodents.