Review
mGlu2/3 Receptor Antagonists as Novel Antidepressants

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Data suggest that the glutamatergic system is an attractive target for the development of novel antidepressants.

Preclinical evidence suggests that metabotropic glutamate (mGlu) 2/3 receptor antagonists exert rapid and sustained antidepressant effects, even in models with depression refractory to treatment with conventional antidepressants.

Increased synaptogenesis, increased activity of certain serotonergic pathways, and increased mesolimbic dopaminergic neuronal signaling, which are all triggered by AMPA receptor stimulation, may also be involved in the antidepressant effects of mGlu2/3 receptor antagonists. All of these synaptic and neural mechanisms underlying the antidepressant effects of mGlu2/3 receptor antagonists are shared by ketamine.

mGlu2/3 receptor antagonists additionally exert anxiolytic and pro-cognitive effects in animal models, both of which are beneficial for the treatment of depression.

Based on the discovery of the robust antidepressant effects of ketamine in patients with depression, including those with treatment-resistant depression, agents acting on the glutamatergic system have drawn much attention as potential novel antidepressants. Among the agents acting on the glutamatergic system, preclinical data have indicated that the group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3, are attractive targets for the development of novel antidepressants. The antidepressant effects of mGlu2/3 receptor antagonists have been demonstrated in rodent models, and the synaptic and neural mechanisms underlying the antidepressant effects of these compounds have been investigated. Furthermore, these findings have indicated the similarities of the antidepressant effects and of the mechanisms underlying these effects between mGlu2/3 receptor antagonists and ketamine. Based on the results obtained hitherto, here I discuss the potential for mGlu2/3 receptor antagonists to be developed as next-generation antidepressants.

Section snippets

The Glutamatergic System as a Target for the Development of Antidepressants

All currently available antidepressant medication, including selective serotonin reuptake inhibitors (SSRIs) and serotonin- and noradrenaline reuptake inhibitors (SNRIs), which act on the monoaminergic system, were developed from studies of the mechanisms of actions of serendipitously discovered drugs. However, more than 30% of patients with depression remain resistant to a series of treatment and, furthermore, several weeks are often required for the full-blown antidepressant effects of these

The mGlu2/3 Receptor and mGlu2/3 Receptor Antagonists

mGlu receptors comprise eight subtypes that are classified into three groups. These receptors belong to the family C G-protein-coupled receptors (GPCRs), which have relatively large N-terminal extracellular domains containing a ligand recognition site to which the endogenous ligand glutamate binds 8, 9. Of these, group II mGlu receptors (mGlu2 and mGlu3 receptors) are coupled to Gi/Go to negatively regulate adenylyl cyclase activity, and are highly expressed within the cortical and limbic

Antidepressant Effects in Animal Models

Antidepressant effects of the mGlu2/3 receptor antagonists in animal models have been demonstrated, for the first time, in the forced swimming test (FST) and tail suspension test (TST) [20]. Importantly, these effects were observed at doses that did not affect the locomotor activities of the animal. Since then, accumulating evidence has confirmed the antidepressant activities of mGlu2/3 receptor antagonists in several animal models, including on the mechanisms implicated in the etiology or

Mechanisms of Action

In 2005, it was reported for the first time that the antidepressant effects of the mGlu2/3 receptor antagonists were mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor stimulation [40]. The role of AMPA receptor stimulation has since been confirmed by many other studies 16, 22, 29, 41, and positive allosteric modulators of the AMPA receptor have also been reported to exert antidepressant effects [42]. Furthermore, the mGlu2/3 receptor antagonists share this

Anxiolytic Effects

Anxiety is commonly encountered in patients with depression, and is associated with greater symptom severity, impairment, and dysfunction in these patients 63, 64; comorbid anxiety symptoms are also known to be associated with worsened pharmacological treatment outcomes [65]. Therefore, efficacy against anxiety symptoms is potentially beneficial for depression treatment. In addition to exerting antidepressant activity, mGlu2/3 receptor antagonists have also been reported to exert anxiolytic

Concluding Remarks

Ever since 2004, when mGlu2/3 receptor antagonists were demonstrated to exert antidepressant effects in animal models, accumulating evidence has indicated that synaptic and neural mechanisms underlying the antidepressant effects may be shared between mGlu2/3 receptor antagonists and ketamine. Consistent with these findings, mGlu2/3 receptor antagonists have been shown to exert ketamine-like antidepressant effects, namely, rapid and sustained antidepressant effects, in rodents. In addition,

Disclaimer Statement

The author is an employee of Taisho Pharmaceutical Co., Ltd.

Will mGlu2/3 receptor antagonists be effective in patients with depression, including those with treatment-resistant depression?

Will mGlu2/3 receptor antagonists exert rapid antidepressant actions in patients with depression similar to those seen with ketamine?

Will mGlu2/3 receptor antagonists improve anxiety symptoms and cognitive dysfunction in patients with depression?

What type of anxiety symptoms would mGlu2/3 receptor antagonists

Acknowledgments

The author acknowledges Dr. Daiji Kambe for his artwork used in the Figures.

Glossary

Allosteric sites
binding sites distinct from the binding sites for endogenous ligands.
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor
one of the glutamate receptor subtypes that binds to AMPA, a synthetic amino acid.
Dorsal raphe nucleus (DRN)
the region of the brainstem that contains neurons producing serotonin.
Glutamate
an amino acid that acts as an excitatory neurotransmitter in the central nervous system.
Nucleus accumbens (NAc)
the region of the basal forebrain that has

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