Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system, and glutamatergic neurotransmission is regulated by ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are divided into three families based on sequence homology, their interaction with intracellular signaling cascades, and pharmacological properties: group I (mGluR1 and 5), group II (mGluR2 and 3) and group III (mGluR4, 6, 7, 8) (Conn & Pin, 1997; Coutinho & Knöpfel, 2002). Specifically, the group I mGlu5, is expressed mostly in post-synaptic neurons (Shigemoto et al., 1997; Sistiaga, Herrero, Conquet, & Sánchez-Prieto, 1998; Takumi, Matsubara, Rinvik, & Ottersen, 1999), and is located on the cellular and intracellular membranes (Hubert, Paquet, & Smith, 2001; López-Bendito, Shigemoto, Fairén, & Luján, 2002; O'Malley, Jong, Gonchar, Burkhalter, & Romano, 2003) of glutamatergic (excitatory) neurons, gamma-aminobutyric acid-ergic (GABA-ergic, inhibitory) neurons, and on glial cells in the perisynaptic space (Lavialle et al., 2011; Lujan, Nusser, Roberts, Shigemoto, & Somogyi, 1996). Regions with the highest mGlu5 density in humans are the hippocampus and putamen, followed by the caudate and cerebral cortex (∼10–15% lower than highest density regions), and thalamus (∼45–50% lower than highest density regions), and lowest expression in the cerebellum (∼65% lower than highest density regions) (Daggett et al., 1995).

Signaling through mGlu5s can be potentiated by positive allosteric modulators (PAMs) and inhibited by negative allosteric modulators (NAMs) (Purgert et al., 2014). PAMs enhance the activation of receptors or prevent agonist-related desensitization, while NAMs can be either non-competitive receptor antagonists or inverse agonists. In recent years, allosteric modulation of mGlu5 has gained attention as a potential therapeutic target in the treatment of psychiatric disorders (Ritzén, Mathiesen, & Thomsen, 2005; Rocher et al., 2011). Drugs that target mGlu5 may bring about a therapeutic effect through secondary N-methyl-d-aspartate receptor (NMDAR) modulation, with scaffolding proteins such as Homer, Shank, and PSD-95 playing an important role in the physical proximity of these receptors at the postsynaptic density, as well as impacting signaling mechanisms of both mGlu5 and NMDAR (Piers et al., 2012; Tu et al., 1999). Moreover, activation of mGlu5 potentiates NMDAR activity while mGlu5 NAMs potentiate the effects of NMDAR antagonists (Attucci, Carlà, Mannaioni, & Moroni, 2001; Awad, Hubert, Smith, Levey, & Conn, 2000; Jin, Xue, Mao, & Wang, 2015; Pisani et al., 2001).

Here, we discuss the role of mGlu5 in psychiatric disorders, including mood disorders, trauma and anxiety disorders, as well as substance use disorders (nicotine, cannabis, and alcohol will specifically be discussed) providing information from preclinical animal models, postmortem, and clinical studies. Clinical investigations include magnetic resonance spectroscopy (MRS), but where possible, we specifically highlight positron emission tomography (PET) studies and results from drug trials that have targeted mGlu5. Further, we provide results from our recent investigations and, when conflicting, equivocal, or limited findings are presented, we present potential hypotheses that might unify results.