Review
Roles of glutamate signaling in preclinical and/or mechanistic models of depression

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Abstract

Accumulating evidence suggests that the glutamatergic system plays important roles in the pathophysiology and treatment of major depressive disorder (MDD). Abnormalities in the glutamatergic system are definitely observed in this disorder, and certain glutamatergic agents exhibit antidepressant effects in patients with MDD. In this review, we summarize the preclinical findings suggesting the involvement of glutamate signaling in the pathophysiology and treatment of MDD. Preclinical animal models for depression are often characterized by changes in molecules related to glutamatergic signaling. Some antidepressants exert their effects by affecting glutamatergic system components in animals. Animals with genetically modified glutamatergic function exhibit depression-like behaviors or anti-depressive behavior. In addition, several types of glutamatergic agents have shown antidepressant-like effects in preclinical models for depression. Many types of glutamate receptors (NMDA, AMPA, and metabotropic glutamate receptors) or transporters appear to be involved in the etiology of depression or in the mechanisms of action of antidepressants. These functional proteins related to glutamate signal transduction are potential targets for a new generation of antidepressants with fast-onset effects, such as the NMDA antagonist ketamine.

Research highlights

► Animal models for depression are accompanied by changes in glutamatergic system. ► Some antidepressant treatments affect glutamatergic system in animals. ► Genetically modified animals exhibit depression-like or anti-depressive behavior. ► Some glutamatergic agents exhibit antidepressant effects in animal models.

Introduction

Major depressive disorder (MDD), also called major depression, is a chronic recurring illness, and its lifetime prevalence is approximately 16.6% in the United States (Kessler and Wang, 2008). Unipolar depressive disorders comprise the first and fifth leading causes of disability-adjusted life-years in high-income countries and in low- and middle-income countries, respectively (Lopez and Mathers, 2006). Drugs that increase the synaptic availability of monoamines (serotonin, norepinephrine, and dopamine), including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and dopamine reuptake inhibitors, have been used to treat depression for more than 50 years (Belmaker, 2008, Chen and Skolnick, 2007, López-Muñoz and Alamo, 2009). Nevertheless, these antidepressants require at least 2 weeks to exert their effects, and the treatment guidelines for MDD recommend the continuous use of these antidepressants for 4 to 8 weeks due to their delayed onset of response (Nakajima et al., 2010). These findings suggest that downstream neural adaptation (e.g., the brain-derived neurotrophic factor (BDNF)-TrkB receptor signaling pathway) rather than elevation of synaptic monoamine levels may be responsible for the therapeutic effects of these drugs (Hashimoto, 2010, Lanni et al., 2009, Racagni and Popoli, 2008). The undesirable side effects of currently used antidepressants are frequently the reason for lack of compliance (Racagni and Popoli, 2010). In addition, between one-third and two-thirds of patients do not respond to the first antidepressant prescribed, and treatment-resistant depression represents an area of unmet medical need (Little, 2009, Shelton et al., 2010). Although efforts to develop novel antidepressants have made progress in reducing these side effects, the currently available antidepressants do not show convincing evidence for a shorter delay of onset of therapeutic effects or improved efficacy in the treatment of treatment-resistant patients.

l-glutamic acid (glutamate) is accepted as the major excitatory neurotransmitter in the central nervous system (CNS), and glutamine synthesis from glutamate and ammonia occurs exclusively in glial cells (Hashimoto, 2009a, Hashimoto, 2011) (Fig. 1). Glutamine plays major roles in nitrogen and carbon homeostasis, and in the detoxification of ammonia, in addition to acting as a precursor for the synthesis of glutamate in specialized excitatory neurons (Hashimoto, 2009a, Hashimoto, 2011). Glutamate released from presynaptic neurons can interact with postsynaptic glutamate receptors, including kainate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and N-methyl-D-aspartate (NMDA) receptors. In addition, glutamate can interact with metabotropic glutamate receptors (mGluRs) on presynaptic and postsynaptic neurons (Hashimoto, 2011). The released glutamate is taken up by the surrounding glial cells via excitatory amino acid transporters (EAATs), converted to glutamine, transported back to the presynaptic neurons, and reconverted to glutamate (Hashimoto, 2009a, Hashimoto, 2011).

There is growing evidence that the glutamatergic system plays important roles in the neurobiology and treatment of MDD (Hashimoto, 2009a, Hashimoto, 2011, Mitchell and Baker, 2010, Sanacora, 2009a, Sanacora, 2009b, Skolnick et al., 2009, Zarate et al., 2010). In this article, the authors review the role of glutamate signaling in preclinical and/or mechanistic models of depression.

Section snippets

Blood, cerebrospinal fluid (CSF) and brain levels of glutamate

Several papers have reported altered glutamate levels in the blood, CSF, and brain of patients with MDD. Increased glutamate levels were observed in the serum (Kim et al., 1982) and plasma (Altamura et al., 1993, Mauri et al., 1998, Mitani et al., 2006) of patients with MDD, and antidepressant treatment reduced the serum glutamate levels in patients with MDD (Maes et al., 1998). Although depressive patients have been reported to show higher glutamine levels in the CSF (Levine et al., 2000), a

Antidepressant effects of NMDA receptor antagonists in patients with MDD

The non-competitive NMDA receptor antagonist ketamine has been used as a standard anesthetic agent for many years in both pediatric and adult patients. A single dose of ketamine was reported to exert robust and rapid antidepressant effects in patients with MDD (Berman et al., 2000, Zarate et al., 2006a). The onset of these effects occurred within 2 h postinfusion and the responses were sustained for 1 week in treatment-resistant MDD (Zarate et al., 2006a). Direct targeting of NMDA receptor

Abnormalities of glutamatergic function in animal models of depression

Animal models of depression are widely used to study the pathophysiology of MDD and the mechanisms of action of established and candidate antidepressants. Most animal models of depression are based on stress exposure during brain development or in adulthood, or on genetic manipulations and selective breeding. In this section, the authors review the literature concerning the abnormalities of glutamate signaling in animal models of depression (Table 1).

Olfactory bulbectomy (OB) is an established

Effects of chronic treatments with antidepressants in animal models of depression

Although there are comparatively few reports on the effects of chronic treatments with antidepressants on glutamatergic functions in animal models of depression, the involvement of glutamatergic functions in the efficacy of antidepressants has been reported (Table 3). In a study using OB mice, chronic treatment with amitriptyline was initiated from 14 days after OB and continued for 14 days. OB caused a significant increase in the mGluR1a level. Chronic amitriptyline treatment (10 mg/kg) reversed

Effects of glutamatergic compounds in preclinical and/or mechanistic models of depression

Chemical compounds that intervene in glutamatergic signaling often have effects on depressive behaviors in animals (Fig. 1). The antidepressant effects of glutamatergic agents in preclinical models are summarized in Table 6.

Summary

Monoamine reuptake inhibitors have been used as antidepressants for several decades now. Recent preclinical and clinical studies on depression have placed a spotlight on the roles of glutamatergic signaling in the pathophysiology of MDD and glutamatergic agents that are expected to comprise one of the next generations of antidepressants. A general hypothesis appears to be emerged from multiple lines of clinical and supportive preclinical evidences. It seems that MDD is associated with elevation

Acknowledgments

This study was supported in part by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan (Grant ID: 06–46, to K. H.).

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