Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies

Abstract

The metabotropic glutamatergic receptor subtype 5 (mGluR5) may represent a promising therapeutic target for stress-related psychiatric disorders. Here, we describe mGluR5 findings in stress disorders, particularly major depressive disorder (MDD), highlighting insights from positron emission tomography studies. Positron emission tomography studies report either no differences or lower mGluR5 in MDD, potentially reflecting MDD heterogeneity. Unlike the rapidly acting glutamatergic agent ketamine, mGluR5-specific modulation has not yet shown antidepressant efficacy in MDD and bipolar disorder. Although we recently showed that ketamine may work, in part, through significant mGluR5 modulation, the specific role of mGluR5 downregulation in ketamine's antidepressant response is unclear. In contrast to MDD, there has been much less investigation of mGluR5 in bipolar disorder, yet initial studies indicate that mGluR5-specific treatments may aid in both depressed and manic mood states. The direction of modulation needed may be state dependent, however, limiting clinical feasibility. There has been relatively little study of posttraumatic stress disorder or obsessive-compulsive disorder to date, although there is evidence for the upregulation of mGluR5 in these disorders. However, while antagonism of mGluR5 may reduce fear conditioning, it may also reduce fear extinction. Therefore, studies are needed to determine the role mGluR5 modulation might play in the treatment of these conditions. Further challenges in modulating this prevalent neurotransmitter system include potential induction of significant side effects. As such, more research is needed to identify level and type (positive/negative allosteric modulation or full antagonism) of mGluR5 modulation required to translate existing knowledge into improved therapies.

Keywords: Anxiety; Bipolar disorder; Major depressive disorder; Metabotrobic glutamatergic receptor subtype 5; Positron emission tomography; mGluR5.

Figure 1

mGluR5 expression is modulated with glutamate release in the synapse. A: mGluR5 expressed on the cell surface with low levels of endogenous glutamate. The PET tracer binds to the surface receptors. B: Although glutamate and the PET tracer do not bind to the same location on the mGluR5, when glutamate is released into the synapse, mGluR5 is downregulated/internalized with less receptors being available on the cell surface. Because the PET tracer can bind only to the surface receptors, the binding decreases.

Figure 2

mGluR5 radioligands bind to receptors at the cell surface only. Images adapted from (147). A. In a healthy individual, there is a balance in protein expression and mGluR5 number at the cell surface on the post-synaptic dendrite. B. In PTSD, there is a hypothesized increase in scaffolding protein Shank1, which anchors extra mGluR5s to the cell surface. Thus, although the number of mGluR5s may be the same in the healthy and PTSD brain, due the upregulation in Shank1, and thus increase in mGluR5 on the cell surface, quantification of mGluR5 shows higher receptor density.