The Action of Antidepressants on the Glutamate System: Regulation of Glutamate Release and Glutamate Receptors

doi:10.1016/j.biopsych.2012.11.009

Biological Psychiatry

Volume 73, Issue 12, 15 June 2013, Pages 1180-1188

https://doi.org/10.1016/j.biopsych.2012.11.009 Get rights and content

Recent compelling evidence has suggested that the glutamate system is a primary mediator of psychiatric pathology and also a target for rapid-acting antidepressants. Clinical research in mood and anxiety disorders has shown alterations in levels, clearance, and metabolism of glutamate and consistent volumetric changes in brain areas where glutamate neurons predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these as major factors in psychopathology. Enhancement of glutamate release/transmission, in turn induced by stress/glucocorticoids, seems crucial for structural/functional changes. Understanding mechanisms of maladaptive plasticity may allow identification of new targets for drugs and therapies. Interestingly, traditional monoaminergic-based antidepressants have been repeatedly shown to interfere with glutamate system function, starting with modulation of N-methyl-D-aspartate (NMDA) receptors. Subsequently, it has been shown that antidepressants reduce glutamate release and synaptic transmission; in particular, it was found antidepressants prevent the acute stress-induced enhancement of glutamate release. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression models. Finally, a number of studies over the years have shown that these drugs regulate glutamate receptors, reducing the function of NMDA receptors, potentiating the function of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, and, more recently, exerting variable effects on different subtypes of metabotropic glutamate receptors. The development of NMDA receptor antagonists has opened new avenues for glutamatergic, rapid acting, antidepressants, while additional targets in the glutamate synapse await development of new compounds for better, faster antidepressant action.

Section snippets

Clinical Evidence: Glutamate Levels, Magnetic Resonance, and Neuroimaging Studies

First, changes in glutamate levels have been found in plasma, cerebrospinal fluid, and the brain of MADI patients. A number of studies reported elevated glutamate content and decreased plasma glutamine/glutamate ratios in the plasma of depressed patients 9, 10, 11. Cerebrospinal fluid studies found higher glutamate content in depressed patients (12) and lower glutamate in patients with refractory affective disorder (13). Interestingly, although an early study did not find any significant

Antidepressants Modulate Synaptic Transmission Mediated by α-Amino-3-Hydroxy-Methyl-4-Isoxazole Propionic Acid and N-Methyl-D-Aspartate Receptors

A number of studies have shown that chronic antidepressant treatment of rats reduces excitatory synaptic transmission. Several drugs, including imipramine, citalopram, tianeptine (a neuroprotective antidepressant, serotonin reuptake enhancer), and electroconvulsive shock, attenuated synaptic transmission in FC 46, 47. The magnitude of both α-amino-3-hydroxy-methyl-4-isoxazole propionic acid receptor (AMPAR) and NMDAR dependent components of the field potential were reduced, with the latter to a

Conclusions and Future Perspectives

Recent times have seen a strong revival of research on the involvement of glutamate system in MADI and of investigation of glutamate-based therapeutic approaches, although many unanswered questions remain on how changes in glutamate-related processes mediate pathophysiology or drug mechanisms. There are currently several lines of preclinical/clinical research, investigating the action of molecules that directly target different sites of regulation of the glutamate synapse, including antagonists

References (106)

R.J. Douglas et al.
Mapping the matrix: The ways of neocortex
Neuron
(2007)
B.S. McEwen
Glucocorticoids, depression, and mood disorders: Structural remodeling in the brain
Metabolism
(2005)
G. Sanacora et al.
Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders
Neuropharmacology
(2012)
K. Tokita et al.
Roles of glutamate signaling in preclinical and/or mechanistic models of depression
Pharmacol Biochem Behav
(2012)
H. Mitani et al.
Correlation between plasma levels of glutamate, alanine and serine with severity of depression
Prog Neuropsychopharmacol Biol Psychiatry
(2006)
J. Levine et al.
Increased cerebrospinal fluid glutamine levels in depressed patients
Biol Psychiatry
(2000)
P.T. Francis et al.
Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem
Brain Res
(1989)
K. Hashimoto et al.
Increased levels of glutamate in brains from patients with mood disorders
Biol Psychiatry
(2007)
C. Yüksel et al.
Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders
Biol Psychiatry
(2010)
V. Lorenzetti et al.
Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies
J Affect Disord
(2009)

L. Musazzi et al.

Environmental stress, glucocorticoids and glutamate release: Effects of antidepressant drugs

Neurochem Int

(2011)

A.M. Magariños et al.

Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors

Neuroscience

(1995)

Y. Watanabe et al.

Tianeptine attenuates stress-induced morphological changes in the hippocampus

Eur J Pharmacol

(1992)

J.J. Radley et al.

Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex

Neuroscience

(2004)

J.J. Radley et al.

Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress

Exp Neurol

(2005)

G. Rajkowska et al.

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

Biol Psychiatry

(1999)

R.S. Duman

Depression: A case of neuronal life and death?

Biol Psychiatry

(2004)

P. Skolnick

Antidepressants for the new millennium

Eur J Pharmacol

(1999)

B. Bobula et al.

Repeated administration of antidepressants decreases field potentials in rat frontal cortex

Neuroscience

(2003)

K. Tokarski et al.

Repeated administration of imipramine attenuates glutamatergic transmission in rat frontal cortex

Neuroscience

(2008)

A.T. Michael-Titus et al.

Imipramine and phenelzine decrease glutamate overﬂow in the prefrontal cortex--a possible mechanism of neuroprotection in major depression?

Neuroscience

(2000)

L. Raiteri et al.

Coexistence and function of different neurotransmitter transporters in the plasma membrane of CNS neurons

Prog Neurobiol

(2002)

E. Celano et al.

Selective regulation of presynaptic calcium/calmodulin-dependent protein kinase II by psychotropic drugs

Biol Psychiatry

(2003)

A. Pittaluga et al.

Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus

Neuropharmacology

(2007)

J. Bagley et al.

Temporal dynamics of glutamate efﬂux in the prefrontal cortex and in the hippocampus following repeated stress: Effects of pretreatment with saline or diazepam

Neuroscience

(1997)

L.P. Reagan et al.

The antidepressant agomelatine inhibits stress-mediated changes in amino acid efflux in the rat hippocampus and amygdala

Brain Res

(2012)

T. Hajszan et al.

Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression

Biol Psychiatry

(2009)

R. Martínez-Turrillas et al.

Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment

Neuropharmacology

(2005)

A. Barbon et al.

Regulation of editing and expression of glutamate alpha-amino-propionic-acid (AMPA)/kainate receptors by antidepressant drugs

Biol Psychiatry

(2006)

A. Pilc et al.

Mood disorders: Regulation by metabotropic glutamate receptors

Biochem Pharmacol

(2008)

M. Smiałowska et al.

Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus

Neuropharmacology

(2002)

F. Matrisciano et al.

Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus

Neuropharmacology

(2002)

J.M. Wieronska et al.

Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex

Brain Res

(2007)

R.M. Berman et al.

Antidepressant effects of ketamine in depressed patients

Biol Psychiatry

(2000)

M. Aan Het Rot et al.

Ketamine for depression: Where do we go from here?

Biol Psychiatry

(2012)

N. Li et al.

Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure

Biol Psychiatry

(2011)

S. Maeng et al.

Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors

Biol Psychiatry

(2008)

J. Du et al.

Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action

Drug Discovery Today Ther Strateg

(2006)

X. Li et al.

Anti depressant-like actions of an AMPA receptor potentiator (LY392098)

Neuropharmacology

(2001)

R.M. O'Connor et al.

Metabotropic glutamate receptor 7: At the interface of cognition and emotion

Eur J Pharmacol

(2010)

H. Koike et al.

Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists

Neuropharmacology

(2011)

R.S. Duman et al.

A neurotrophic model for stress-related mood disorders

Biol Psychiatry

(2006)

F. Fonnum

Glutamate: A neurotransmitter in mammalian brain

J Neurochem

(1984)

M. Popoli et al.

The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission

Nat Rev Neurosci

(2012)

J.H. Krystal et al.

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

Mol Psychiatry

(2002)

J.M. Gorman et al.

A hypothesized role for dendritic remodeling in the etiology of mood and anxiety disorders

J Neuropsychiatry Clin Neurosci

(2010)

M.C. Mauri et al.

Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment

Neuropsychobiology

(1998)

E. Küçükibrahimoğlu et al.

The change in plasma GABA, glutamine and glutamate levels in fluoxetine- or S-citalopram-treated female patients with major depression

Eur J Clin Pharmacol

(2009)

M.A. Frye et al.

Low cerebrospinal glutamate release: Effects of antidepressant drugs

Neurochem Int

(2007)

M.J. Lan et al.

Metabonomic analysis identiﬁes molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

Mol Psychiatry

(2009)

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: Authors LM and GT contributed equally to this work.

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ReviewThe Action of Antidepressants on the Glutamate System: Regulation of Glutamate Release and Glutamate Receptors

Section snippets

Clinical Evidence: Glutamate Levels, Magnetic Resonance, and Neuroimaging Studies

Antidepressants Modulate Synaptic Transmission Mediated by α-Amino-3-Hydroxy-Methyl-4-Isoxazole Propionic Acid and N-Methyl-D-Aspartate Receptors

Conclusions and Future Perspectives

Neuron

Metabolism

Neuropharmacology

Pharmacol Biochem Behav

Prog Neuropsychopharmacol Biol Psychiatry

Biol Psychiatry

Brain Res

Biol Psychiatry

Biol Psychiatry

J Affect Disord

Neurochem Int

Neuroscience

Eur J Pharmacol

Neuroscience

Exp Neurol

Biol Psychiatry

Biol Psychiatry

Eur J Pharmacol

Neuroscience

Neuroscience

Neuroscience

Prog Neurobiol

Biol Psychiatry

Neuropharmacology

Neuroscience

Brain Res

Biol Psychiatry

Neuropharmacology

Biol Psychiatry

Biochem Pharmacol

Neuropharmacology

Neuropharmacology

Brain Res

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Drug Discovery Today Ther Strateg

Neuropharmacology

Eur J Pharmacol

Neuropharmacology

Biol Psychiatry

Glutamate: A neurotransmitter in mammalian brain

J Neurochem

The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission

Nat Rev Neurosci

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

Mol Psychiatry

A hypothesized role for dendritic remodeling in the etiology of mood and anxiety disorders

J Neuropsychiatry Clin Neurosci

Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment

Neuropsychobiology

The change in plasma GABA, glutamine and glutamate levels in fluoxetine- or S-citalopram-treated female patients with major depression

Eur J Clin Pharmacol

Low cerebrospinal glutamate release: Effects of antidepressant drugs

Neurochem Int

Metabonomic analysis identiﬁes molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

Mol Psychiatry

Review
The Action of Antidepressants on the Glutamate System: Regulation of Glutamate Release and Glutamate Receptors