glutamate and unipolar depression

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(Updated 9/13/04)

Paul IA, Skolnick P
Glutamate and depression: clinical and preclinical studies.
Ann N Y Acad Sci. 2003 Nov;1003250-72.
The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical models. Moreover, antidepressant-like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants. [Abstract]

Auer DP, Pütz B, Kraft E, Lipinski B, Schill J, Holsboer F
Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study.
Biol Psychiatry. 2000 Feb 15;47(4):305-13.
BACKGROUND: Functional imaging studies suggest a specific role of the anterior brain regions in the pathogenesis of major depression. The aim of this study was to evaluate possible neurochemical alterations in the frontomesial cortex in patients with major depressive episode using in vivo proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Single voxel (1)H-MRS was performed in 19 patients with major depressive episodes and 18 age-matched healthy controls within the anterior cingulate cortex and the parietal white matter. Absolute concentrations were estimated for N-acetyl-aspartate, choline-containing compounds, total creatine, myo-inositol, unresolved glutamate and glutamine (Glx) and glutamate alone (Glu). Voxel composition was analyzed by image segmentation into cerebrospinal fluid (CSF), grey and white matter. RESULTS: MANOVA test for Glx and Glu using age, percent CSF and percent grey matter contribution as covariates yielded a significant group effect within the anterior cingulate due to decrease of Glx in patients (-10.4%, p =.013). Considering only severely depressed patients, both Glx and Glu (-14.3%, p =.03) showed a significant decrease. There was no significant group effect for the neuronal marker NAA, creatine, choline or myo-inositol in either localization. CONCLUSIONS: This study suggests a possible role of altered glutamatergic neurotransmission within the anterior cingulate in the pathogenesis of mood disorders. The otherwise unremarkable findings of major brain metabolites confirms lack of neurodegenerative or membrane metabolic changes in major depression. [Abstract]

Mirza Y, Tang J, Russell A, Banerjee SP, Bhandari R, Ivey J, Rose M, Moore GJ, Rosenberg DR
Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression.
J Am Acad Child Adolesc Psychiatry. 2004 Mar;43(3):341-8.
OBJECTIVE: To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of children with major depressive disorder (MDD). METHOD: Single-voxel proton magnetic resonance spectroscopic (H-MRS) examinations of the anterior cingulate cortex were conducted in 13 psychotropic-naïve children and adolescents with MDD and 13 age- and sex-matched healthy children and adolescents. Ten of the 13 MDD patient-control pairs also had a H-MRS examination of occipital cortex. RESULTS: Anterior cingulate glutamatergic (Glx) concentrations were significantly lower (19% decrease) in MDD patients versus controls (9.27 +/- 0.43 versus 11.47 +/- 0.26, respectively, p = 0.000). Reduced anterior cingulate Glx in MDD patients was associated with increased severity of functional impairment. These results remained comparably significant after controlling for age and anterior cingulate volume. Occipital cortex Glx did not differ between MDD patients and controls. CONCLUSIONS: These preliminary findings provide new evidence of localized functional neurochemical marker alterations in Glx in anterior cingulate cortex in pediatric MDD. Altered anterior cingulate Glx neurotransmission may be involved in the pathogenesis of MDD. [Abstract]

Rosenberg DR, Mirza Y, Russell A, Tang J, Smith JM, Banerjee SP, Bhandari R, Rose M, Ivey J, Boyd C, Moore GJ.
Reduced Anterior Cingulate Glutamatergic Concentrations in Childhood OCD and Major Depression Versus Healthy Controls.
J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1146-1153.
OBJECTIVE:: To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of pediatric patients with obsessive-compulsive disorder (OCD) without major depressive disorder (MDD) versus pediatric patients with MDD without OCD and healthy controls. METHOD:: Single-voxel proton magnetic resonance spectroscopic examinations of the anterior cingulate cortex were conducted in 14 psychotropic-naive children and adolescents with MDD without OCD, 10 to 19 years of age, 14 case-matched healthy controls, and 20 nondepressed, psychotropic-naive pediatric patients with OCD 7 to 19 years of age. RESULTS:: Anterior cingulate glutamatergic concentrations were significantly reduced in both patients with OCD (15.1% decrease) and patients with MDD (18.7% decrease) compared with controls. Anterior cingulate glutamatergic concentrations did not differ significantly between patients with OCD and those with MDD. CONCLUSIONS:: Altered anterior cingulate glutamatergic neurotransmission may be involved in the pathogenesis of OCD and MDD. These preliminary findings further suggest that reduced anterior cingulate glutamate does not differentiate pediatric patients with OCD from pediatric patients with MDD. [Abstract]

Pfleiderer B, Michael N, Erfurth A, Ohrmann P, Hohmann U, Wolgast M, Fiebich M, Arolt V, Heindel W
Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients.
Psychiatry Res. 2003 Apr 1;122(3):185-92.
Cortical glutamate/glutamine (Glx) metabolism seems to be affected by a major depressive disorder. Recently, a Glx deficit was detected by proton magnetic resonance spectroscopy (1H-MRS) in the bilateral anterior cingulum of depressives. The aim of this study was to assess the effect of successful electroconvulsive therapy (ECT) on Glx levels in the anterior cingulum. The left anterior cingulum of 17 severely depressed unipolar patients was measured by 1H STEAM spectroscopy before and after ECT, and the results were compared with those for 17 age- and gender-matched controls. We observed significantly reduced Glx levels in the patients' left cingulum compared to healthy controls. In ECT responders, in contrast to non-responders, Glx levels normalized (P=0.04) and then did not differ statistically from controls. Severe depression seems to be associated with a Glx deficit and increasing Glx may be an important mechanism of ECT action. [Abstract]

Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF
Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.
Arch Gen Psychiatry. 2004 Jul;61(7):705-13.
BACKGROUND: Measurement of cortical gamma-aminobutyric acid (GABA) and glutamate concentrations is possible using proton magnetic resonance spectroscopy. An initial report, using this technique, suggested that occipital cortex GABA concentrations are reduced in patients with major depressive disorder (MDD) relative to healthy comparison subjects. OBJECTIVES: To replicate the GABA findings in a larger sample of MDD patients, to examine the clinical correlates of the GABA reductions in these subjects, and to examine other critical metabolite levels. DESIGN: Study for association. SETTING: Academic clinical research program. PARTICIPANTS: The GABA measurements were made on 38 healthy control subjects and 33 depressed subjects. INTERVENTIONS: Occipital cortex metabolite levels were measured using proton magnetic resonance spectroscopy. MAIN OUTCOME MEASURES: The levels of occipital cortex GABA, glutamate, N-acetylaspartate, aspartate, creatine, and choline-containing compounds, along with several measures of tissue composition, were compared between the 2 groups. RESULTS: Depressed subjects had significantly lower occipital cortex GABA concentrations compared with healthy controls (P =.01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with healthy controls (P<.001). Significant reductions in the percentage of solid tissue (P =.009) and the percentage of white matter (P =.04) in the voxel were also observed. An examination of a combined database including subjects from the original study suggests that GABA and glutamate concentrations differ among MDD subtypes. CONCLUSIONS: The study replicates the findings of decreased GABA concentrations in the occipital cortex of subjects with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory neurotransmitter levels in the cortex of depressed subjects that may be related to altered brain function. Last, the combined data set suggests that magnetic resonance spectroscopy GABA measures may serve as a biological marker for a subtype of MDD. [Abstract]

Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B
Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression.
Psychol Med. 2003 Oct;33(7):1277-84.
BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) is involved in the pathophysiology of major depression. In particular, metabolic (functional hypometabolism) and structural alterations have been described. In this study metabolic changes within the DLPFC of severely depressed patients before and after electroconvulsive therapy (ECT) were evaluated by proton STEAM spectroscopy (1H-MRS). METHOD: Twelve severely depressed patients with a diagnosis of major depressive episode, unipolar with melancholic features (DSM-IV), were enrolled, and the left dorsolateral prefrontal cortex (DLPFC) was investigated before and after unilateral ECT by 1H-MRS. Three of the four non-responding patients were remeasured a third time after a combined ECT/antidepressant pharmacotherapy. The results were compared with 12 age- and gender-matched controls. RESULTS: In depressed patients reduced glutamate/glutamine (Glx) levels were measured pre-ECT; Glx concentrations correlated negatively with severity of depression. After successful treatment, Glx increased significantly and levels no longer differed from those of age-matched controls. CONCLUSIONS: Our results indicate that major depressive disorder is accompanied by state-dependent metabolic alterations, especially in glutamate/glutamine metabolism, which can be reversed by successful ECT. [Abstract]

Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B
Neurotrophic effects of electroconvulsive therapy: a proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression.
Neuropsychopharmacology. 2003 Apr;28(4):720-5.
Negatively balanced neurotrophic factors may be important in precipitating clinical depression. Recently, it has been reported that antidepressant therapy may exert positive neurotrophic effects. The aim of this study was to detect probable neurotrophic changes during electroconvulsive therapy (ECT). For this purpose, N-acetylaspartate (NAA), an amino acid exclusively located in neurons, and other brain metabolites such as glutamine/glutamate (Glx), choline (Cho), and creatine (Cr) were measured in patients by localized proton magnetic resonance spectroscopy. A total of 28 severely depressed patients (DSM-IV) were enrolled, and the left amygdalar region was investigated by proton STEAM spectroscopy before and after unilateral ECT. The results were compared with 28 age- and gender-matched controls using nonparametric paired and unpaired tests. A significant increase in NAA was observed only in ECT responders (n=14; p=0.019). Five out of 14 nonresponders to ECT monotherapy were remeasured following a clinical improvement after continued ECT combined with antidepressants and were then found also to present a significant increase in NAA. In all successfully treated patients, parallel observations, that is, increased levels, were made for Glx, whereas Cho and Cr were unchanged. In conclusion, our preliminary finding of increased NAA concentrations after successful ECT may indicate a probable neurotrophic effect of ECT. [Abstract]

Sapolsky RM
The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death.
Biol Psychiatry. 2000 Oct 15;48(8):755-65.
A number of studies indicate that prolonged, major depression is associated with a selective loss of hippocampal volume that persists long after the depression has resolved. This review is prompted by two ideas. The first is that overt neuron loss may be a contributing factor to the decrease in hippocampal volume. As such, the first half of this article reviews current knowledge about how hippocampal neurons die during insults, focusing on issues related to the trafficking of glutamate and calcium, glutamate receptor subtypes, oxygen radical generation, programmed cell death, and neuronal defenses. This is meant to orient the reader toward the biology that is likely to underlie any such instances of neuron loss in major depression. The second idea is that glucocorticoids, the adrenal steroids secreted during stress, may play a contributing role to any such neuron loss. The subtypes of depression associated with the hippocampal atrophy typically involve significant hypersecretion of glucocorticoids, and the steroid has a variety of adverse effects in the hippocampus, including causing overt neuron loss. The second half of this article reviews the steps in this cascade of hippocampal neuron death that are regulated by glucocorticoids. [Abstract]

Nowak G
Does interaction between zinc and glutamate system play a significant role in the mechanism of antidepressant action?
Acta Pol Pharm. 2001 Jan-Feb;58(1):73-5.
In the central nervous system, zinc modulates predominantly the excitatory amino acid (glutamatergic) neurotransmission. Recent studies demonstrated that chronic antidepressant treatment, which is required for clinical improvement, reduced the reactivity/function of the glutamate/NMDA receptor complex and altered zinc concentration/interaction with this receptor type in the rodent brain. In the cerebral cortex: chronic antidepressant treatment "down-regulated" (reduced density/affinity) of the cortical (but not hippocampal) NMDA receptors measured by radioligand-receptor binding methods. Moreover, chronic imipramine treatment increased the ability of zinc ion to inhibit the NMDA receptor complex in the cerebral cortex but not in the hippocampus. In the hippocampus: chronic treatment with antidepressant drugs (imipramine or citalopram) increased the hippocampus/brain region ratio of zinc concentration, which may indicate redistribution of the rat brain zinc. On the other hand, electroconvulsive shocks induced robust increase of zinc concentration in the hippocampus (with a slight effect in the rest of brain). In spite of the lack of alterations in the hippocampal NMDA receptors (measured by receptor binding methods), inhibitory effect of the increased hippocampal zinc concentration induced by chronic antidepressant treatment, may be responsible for reduction in the function of that receptor complex also in the hippocampus. These data indicate a critical and complex role of the interaction between zinc and NMDA receptor complex in the mechanism of antidepressant treatment and strongly support the glutamate hypothesis of the mechanism of antidepressant action. [Abstract]

Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R
Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression.
Pharmacopsychiatry. 1996 Jan;29(1):23-6.
NMDA antagonists mimic the effects of clinically effective antidepressants in both preclinical tests predictive of antidepressant action and procedures designed to model aspects of depressive symptomatology. These findings led to experiments demonstrating that chronic administration of NMDA antagonists to rodents results in a downregulation of cortical beta-adrenoceptors, a phenomenon also observed following chronic treatment with many antidepressants. These neurochemical and behavioral similarities between antidepressants and NMDA antagonists prompted us to examine the impact of chronic antidepressant treatment on NMDA receptors. Chronic (14 days) but not acute (1 day) administration of seventeen different antidepressants to mice produced adaptive changes in radioligand binding to NMDA receptors. Detailed studies with three antidepressants (imipramine, citalopram, and electroconvulsive shock) show that these changes develop slowly, persist for some time after cessation of treatment, and (for imipramine and citalopram) are dose dependent. Moreover, following chronic treatment with imipramine, these changes in radioligand binding to NMDA receptors appear restricted to the cerebral cortex. Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action. The recent demonstration (Nowak et al., 1995) that radioligand binding to NMDA receptors is altered in frontal cortex of suicide victims (compared to age and post-mortem interval matched controls) is consistent with the hypothesis (Trullas and Skolnick, 1990) that this family of ligand gated ion channels is involved in the pathophysiology of depression. [Abstract]

Michael-Titus AT, Bains S, Jeetle J, Whelpton R
Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex--a possible mechanism of neuroprotection in major depression?
Neuroscience. 2000;100(4):681-4.
Antidepressant drugs have been used for decades, but the neurobiological substrate of their efficacy is not completely understood. Although these drugs have well-established effects on monoamines, evidence is emerging that they may also affect other neurotransmitter systems. It has been shown that treatment with a wide range of antidepressants changes the binding characteristics of the N-methyl-D-aspartate type of glutamate receptor. This change is delayed and occurs only in the cortex. The mechanism that triggers it is unknown. We hypothesized that N-methyl-D-aspartate receptor alterations may be due to changes in the dynamics of cortical excitatory amino acid release. Such changes are of particular interest in areas such as the prefrontal cortex, a region involved in stress responses and affected in major depression. We investigated the effects of two antidepressants with different modes of action, imipramine and phenelzine, on glutamate and aspartate outflow in rat prefrontal cortex and striatum. We showed that antidepressants significantly decreased stimulated glutamate outflow. The effect had a rapid onset, was sustained during chronic administration and was only seen in the prefrontal cortex. This change may initiate receptor alterations. Furthermore, if antidepressants can dampen states of hyperglutamatergic activity and the subsequent excitotoxicity, their chronic use may have a considerable neuroprotective potential in major depression. [Abstract]

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH
Antidepressant effects of ketamine in depressed patients.
Biol Psychiatry. 2000 Feb 15;47(4):351-4.
BACKGROUND: A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. METHODS: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. RESULTS: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). CONCLUSIONS: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression. [Abstract]

Kudoh A, Takahira Y, Katagai H, Takazawa T
Small-dose ketamine improves the postoperative state of depressed patients.
Anesth Analg. 2002 Jul;95(1):114-8, table of contents.
We investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery. We studied 70 patients with major depression and 25 patients as the control (Group C). The depressed patients were divided randomly into two groups; patients in Group A (n = 35) were induced with propofol, fentanyl, and ketamine and patients in Group B (n = 35) were induced with propofol and fentanyl, and all patients were maintained with 1.5%-2.0% isoflurane plus nitrous oxide. The mean Hamilton Depression Rating (HDR) score was 12.7 +/- 5.4 for Group A and 12.3 +/- 6.0 for Group B 2 days before surgery and 9.9 +/- 4.1 for Group A and 14.4 +/- 3.8 for Group B 1 day after surgery. The HDR score in Group A 1 day after surgery was significantly (P < 0.05) lower than that in Group B. The HDR score in Group C was 4.2 +/- 1.7 2 days before surgery and 4.8 +/- 1.6 1 day after surgery. Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in Group A as compared with Group B. Postoperative pain scores in Group A at 8 and 16 h after the end of anesthesia were 26.6 +/- 8.7 and 24.9 +/- 8.2, respectively, which were significantly (P < 0.05) lower than 34.3 +/- 12.0 and 31.1 +/- 8.8 in Group B. In conclusion, small-dose ketamine improved the postoperative depressive state and relieved postoperative pain in depressed patients. IMPLICATIONS: NMDA receptor antagonists are reported to be effective for improving depression. It remains unclear whether ketamine, which is an NMDA receptor antagonist, postoperatively affects the psychological state in depressed patients. We investigated the effect of 1.0 mg/kg of ketamine on postoperative outcomes in depressed patients. [Abstract]

Joanny P, Steinberg J, Oliver C, Grino M.
Glutamate and N-methyl-D-aspartate stimulate rat hypothalamic corticotropin-releasing factor secretion in vitro.
J Neuroendocrinol. 1997 Feb;9(2):93-7.
It is known that in vivo excitatory amino acids (EAA) stimulate the hypothalamo-pituitary-adrenal axis. However their site of action is not fully understood. We investigated the possibility of a direct action of EAA on the secretion of the major adrenocorticotropin hormone (ACTH) secretagogue: corticotropin-releasing factor (CRF) from incubated rat hypothalamic slices. N-methyl-D-aspartic acid (NMDA) or L-glutamate (1 x 10(-7) to 1 x 10(-3) M) stimulated in a dose-dependent fashion CRF release. The maximal effect was obtained at a concentration of 1 x 10(-4) M for both drugs. The IC50 was 1.3 x 10(-5) M and 3.3 x 10(-5) M for NMDA and L-glutamate, respectively. Incubation with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist) or 2-amino-4-phosphonobutyrate (a metabotropic receptor antagonist) was without significant effect on basal CRF secretion and completely blocked the increase in CRF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M AMPA did not change basal CRF secretion. Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of kainate and AMPA receptor) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAA could stimulate directly CRF secretion, by an action through NMDA and metabotropic receptors, but not kainate or AMPA receptors. These findings may be relevant to the regulation of the hypothalamo-pituitary adrenal axis, both under basal conditions and during exposure to stress. [Abstract]

Berk M, Plein H, Ferreira D
Platelet glutamate receptor supersensitivity in major depressive disorder.
Clin Neuropharmacol. 2001 May-Jun;24(3):129-32.
Dysregulation of glutamate has been described in depression, and supersensitivity of platelet glutamate receptors has been found in both psychotic major depression and schizophrenia. The aim of this study was to examine the platelet glutamate receptor sensitivity in patients with nonpsychotic, unipolar major depression to assess whether this is a marker of depression or of psychosis. Glutamate receptor sensitivity was assessed using the platelet intracellular calcium response to glutamate (0-100 micromol) measured by spectrofluorometry. The depression group showed a significantly greater platelet intracellular calcium response to glutamate stimulation than the control group, both in terms of absolute values (p = 0.007) and percentage of response from baseline (p = 0.030). These data suggest that platelet glutamate receptors may be supersensitive in depression and that the platelet may be a possible peripheral marker of glutamate function in depression. [Abstract]

Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, Invernizzi G
Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment.
Neuropsychobiology. 1998;37(3):124-9.
Plasma and platelet levels of 18 amino acids were measured in 29 outpatients (mean age +/- SD 47.41 +/- 10.85 years; 14 F, 15 M) affected by major depression (DSM IV) and in 28 healthy volunteers (mean age 42.46 +/- 14.19 years; 12 F, 16 M). Plasma and platelet levels of amino acids tended to be higher in depressed patients than in healthy controls. In particular, glutamate, taurine and lysine plasma levels and aspartate, serine and lysine platelet levels were significantly higher. Tryptophan/large neutral amino acids ratio (trp/LNAAs) was significantly lower in depressed patients. Fluvoxamine treatment did not influence plasma and platelet levels of amino acids or trp/LNAAs ratio. [Abstract]

Maes M, Verkerk R, Vandoolaeghe E, Lin A, Scharpé S
Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity.
Acta Psychiatr Scand. 1998 Apr;97(4):302-8.
Previous research has revealed that major depression is accompanied by disorders in excitatory amino acids, e.g. glutamate and aspartate, and alterations in serum levels of other amino acids, e.g. serine, glycine and taurine. The aim of the present study was to examine serum levels of aspartate, asparagine, glutamate, glutamine, serine, glycine, threonine, histidine, alanine, taurine and arginine in major depression patients with treatment-resistant depression (TRD). No significant differences in the serum concentrations of any of the above amino acids could be found between patients with and without TRD and normal controls. Non-responders to treatment with antidepressants during a period of 5 weeks were characterized by significantly lower serum levels of aspartate, asparagine, serine, threonine and taurine. A 5-week period of treatment with antidepressants significantly reduced the serum levels of aspartate, glutamate and taurine, and significantly increased the serum concentrations of glutamine. The results suggest that alterations in serum levels of aspartate, asparagine, serine, threonine and taurine may predict the subsequent response to treatment with antidepressants, and that the latter may modulate serum levels of excitatory amino acids and taurine. [Abstract]

Altamura C, Maes M, Dai J, Meltzer HY
Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression.
Eur Neuropsychopharmacol. 1995;5 Suppl71-5.
This study was carried out to investigate plasma levels of excitatory amino acids, such as glutamate and aspartate, and glutamine, serine, glycine, taurine and histidine in major depression. The plasma amino acids were determined by means of HPLC in 22 normal controls and 25 unmedicated patients with major depression. Major depression was characterized by higher plasma taurine levels than normal controls. Significantly lower plasma glycine values and a higher serine/glycine ratio were observed in the depressed group. No significant differences in glutamine, histidine, serine or aspartate levels could be detected between the study groups. By means of linear discriminant analysis, a highly significant separation between major depressed subjects and normal volunteers was found using glycine, glutamate and taurine as discriminatory variables. No significant relationships between any of the amino acids and severity of depression could be found. The results suggest that major depression is accompanied by perturbations in the serine/glycine ratio, excitatory amino acids, such as glutamate, and inhibitory amino acids, such as taurine. [Abstract]

Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW
Increased cerebrospinal fluid glutamine levels in depressed patients.
Biol Psychiatry. 2000 Apr 1;47(7):586-93.
BACKGROUND: There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS: We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS: Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS: These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression. [Abstract]

McCullumsmith RE, Meador-Woodruff JH
Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder.
Neuropsychopharmacology. 2002 Mar;26(3):368-75.
Because abnormalities of glutamatergic neurotransmission in psychiatric illness are likely not limited to glutamate receptor expression, we investigated expression of excitatory amino acid transporters (EAATs) in the striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic lateral sclerosis, and schizophrenia. In this study, we investigated striatal expression of transcripts encoding EAATs in tissue from mood disordered and schizophrenic subjects. With probes designed for the human EAAT1, EAAT2, EAAT3, and EAAT4 transcripts, we performed in situ hybridization and detected decreased expression of EAAT3 and EAAT4 transcripts in the striatum in bipolar disorder. We also detected decreased EAAT3 transcript expression in schizophrenia and decreased EAAT4 transcript expression in major depressive disorder. These results suggest that changes in striatal transporter mRNA expression are restricted to neuronal EAATs and extend the body of evidence implicating abnormal glutamatergic neurotransmission in schizophrenia and mood disorders. [Abstract]

Francis PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR, Procter AW, Bruton CJ, Bowen DM
Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem.
Brain Res. 1989 Aug 14;494(2):315-24.
The concentrations of 3 putative neurotransmitters (glutamate, aspartate and gamma-aminobutyrate), 4 related amino acids and 5 non-transmitter-related amino acids have been measured in neurosurgical samples (frontal cortex) from patients with intractable depression and controls. In addition, the glutamate receptor agonist 2-amino-4-sulpho-butanoic acid (homocysteic acid) has been identified in human brain and measured in these samples. There were no changes in the concentrations of amino acids in depressed patients compared to control with the exception of aspartic and homocysteic acids which were elevated in a sub-group of patients with depression compared to control. The Ca2+-dependent release (K+-stimulated) of putative neurotransmitters has been demonstrated for the first time from brain tissue of depressed patients. Glutamate release was unaltered from the control value. Aspartate values showed unexplained variability but it's release and that of gamma-aminobutyrate were elevated in some depressed subjects. These results do not support the hypothesis of reduced amino acid function in depressive illness. [Abstract]

Meador-Woodruff JH, Hogg AJ, Smith RE
Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.
Brain Res Bull. 2001 Jul 15;55(5):631-40.
Abnormalities of the ionotropic glutamate receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid [AMPA], and kainate) have been reported in the brain in schizophrenia, although in complex, region-specific patterns. While limbic cortex and medial temporal lobe structures have been most often studied in psychiatric illnesses, glutamate receptors are expressed in other brain regions associated with limbic circuitry, especially the striatum. In this study, we have determined striatal ionotropic glutamate receptor expression in brains from persons with schizophrenia, bipolar disorder, major depression, and a comparison group, using samples from the Stanley Foundation Neuropathology Consortium. We have determined the expression of these receptors at multiple levels of gene expression by using both in situ hybridization and receptor autoradiography. The expression of nearly all of these molecules was not different in these psychiatric conditions. The only significant changes noted were NR2D and gluR1 transcripts, and [(3)H]AMPA binding. This is the first comprehensive study of striatal ionotropic glutamate receptor expression in schizophrenia and affective disorders, and suggests that there are minimal changes in these receptors in this region of the brain in these illnesses. [Abstract]

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Recent Glutamate and Depression Research

1) Dhir A, Kulkarni SK
Nitric oxide and major depression.
Nitric Oxide. 2011 Apr 30;24(3):125-31.
Nitric oxide has been known to play a significant role in the pathophysiology of various disorders of the body. Despite its very short half-life, nitric oxide is known to modulate various neurotransmitter system(s) in the body and thus is speculated to play an imperative role in the pathogenesis of neurological disorders. This "wonder" molecule has been often found to possess a "dual role" in many neurological disorders of the body. Evidences have shown its prominent role in the pathogenesis of major depression. Nitric oxide modulates norepinephrine, serotonin, dopamine, glutamate, the major neurotransmitters involved in the neurobiology of major depression. The nitric oxide modulatory activity of various new generations of antidepressants has been demonstrated. Clinical studies have also confirmed the nitric oxide modulatory activity of various antidepressants particularly belonging to the class of selective serotonin reuptake inhibitors. The present review attempts to discuss the role of nitric oxide in the pathophysiology of major depression. Further, the involvement of nitric oxide system in the mechanism of various antidepressants has been discussed in detail. Nitric oxide based antidepressants can be the future drugs of choice for major depression, particularly in the treatment of pharmacoresistant depression. [PubMed Citation] [Order full text from Infotrieve]

2) Kim SS, Wang H, Li XY, Chen T, Mercaldo V, Descalzi G, Wu LJ, Zhuo M
Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice.
Mol Brain. 2011;4:6.
ABSTRACT: Affective disorders, which include anxiety and depression, are highly prevalent and have overwhelming emotional and physical symptoms. Despite human brain imaging studies, which have implicated the prefrontal cortex including the anterior cingulate cortex (ACC), little is known about the ACC in anxiety disorders. Here we show that the ACC does modulate anxiety-like behavior in adult mice, and have identified a protein that is critical for this modulation. Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior. Selective inhibition of neurabin in the ACC reproduced the anxiety but not the depression phenotype. Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability. These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders. [PubMed Citation] [Order full text from Infotrieve]

3) Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, Krystal JH, Sanacora G
The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS.
Psychiatry Res. 2011 Feb 28;191(2):122-7.
The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([(1)H]-MRS) method that previously detected a normalization of amino acid neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [(1)H] MRS scans (baseline, 3h and 48 h post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1h) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements. [PubMed Citation] [Order full text from Infotrieve]

4) Schmidt MV, Trümbach D, Weber P, Wagner K, Scharf SH, Liebl C, Datson N, Namendorf C, Gerlach T, Kühne C, Uhr M, Deussing JM, Wurst W, Binder EB, Holsboer F, Müller MB
Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus.
J Neurosci. 2010 Dec 15;30(50):16949-58.
Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function. [PubMed Citation] [Order full text from Infotrieve]

5) Hoyle D, Juhasz G, Aso E, Chase D, del Rio J, Fabre V, Hamon M, Lanfumey L, Lesch KP, Maldonado R, Serra MA, Sharp T, Tordera R, Toro C, Deakin JF
Shared changes in gene expression in frontal cortex of four genetically modified mouse models of depression.
Eur Neuropsychopharmacol. 2011 Jan;21(1):3-10.
This study aimed to identify whether genetic manipulation of four systems implicated in the pathogenesis of depression converge on shared molecular processes underpinning depression-like behaviour in mice. Altered 5HT function was modelled using the 5-HT transporter knock out mouse, impaired glucocorticoid receptor (GR) function using an antisense-induced knock down mouse, disrupted glutamate function using a heterozygous KO of the vesicular glutamate transporter 1 gene, and impaired cannabinoid signalling using the cannabinoid 1 receptor KO mouse. All 4 four genetically modified mice were previously shown to show exaggerated helpless behaviour compared to wild-type controls and variable degrees of anxiety and anhedonic behaviour. mRNA was extracted from frontal cortex and hybridised to Illumina microarrays. Combined contrast analysis was used to identify genes showing different patterns of up- and down-regulation across the 4 models. 1823 genes were differentially regulated. They were over-represented in gene ontology categories of metabolism, protein handling and synapse. In each model compared to wild-type mice of the same genetic background, a number of genes showed increased expression changes of >10%, other genes showed decreases in each model. Most of the genes showed mixed effects. Several previous array findings were replicated. The results point to cellular stress and changes in post-synaptic remodelling as final common mechanisms of depression and resilience. [PubMed Citation] [Order full text from Infotrieve]

6) Tordera RM, Garcia-García AL, Elizalde N, Segura V, Aso E, Venzala E, Ramírez MJ, Del Rio J
Chronic stress and impaired glutamate function elicit a depressive-like phenotype and common changes in gene expression in the mouse frontal cortex.
Eur Neuropsychopharmacol. 2011 Jan;21(1):23-32.
Major depression might originate from both environmental and genetic risk factors. The environmental chronic mild stress (CMS) model mimics some environmental factors contributing to human depression and induces anhedonia and helplessness. Mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1) have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, gene expression changes in the frontal cortex, common to stress and impaired glutamate function. Both VGLUT1(+/-) and CMS mice showed helpless and anhedonic-like behavior. Microarray studies in VGLUT1(+/-) mice revealed regulation of genes involved in apoptosis, neurogenesis, synaptic transmission, protein metabolic process or learning and memory. In addition, RT-PCR studies confirmed gene expression changes in several glutamate, GABA, dopamine and serotonin neurotransmitter receptors. On the other hand, CMS affected the regulation of 147 transcripts, some of them involved in response to stress and oxidoreductase activity. Interestingly, 52 genes were similarly regulated in both models. Specifically, a dowregulation in genes that promote cell proliferation (Anapc7), cell growth (CsnK1g1), cell survival (Hdac3), and inhibition of apoptosis (Dido1) was observed. Genes linked to cytoskeleton (Hspg2, Invs), psychiatric disorders (Grin1, MapK12) or an antioxidant enzyme (Gpx2) were also downregulated. Moreover, genes that inhibit the MAPK pathways (Dusp14), stimulate oxidative metabolism (Eif4a2) and enhance glutamate transmission (Rab8b) were upregulated. We suggest that these genes could form part of the altered "molecular context" underlying depressive-like behaviour in animal models. The clinical relevance of these findings is discussed. [PubMed Citation] [Order full text from Infotrieve]

7) Portella MJ, de Diego-Adeliño J, Gómez-Ansón B, Morgan-Ferrando R, Vives Y, Puigdemont D, Pérez-Egea R, Ruscalleda J, Enric Álvarez V, Pérez
Ventromedial prefrontal spectroscopic abnormalities over the course of depression: a comparison among first episode, remitted recurrent and chronic patients.
J Psychiatr Res. 2011 Apr;45(4):427-34.
Structural and neuropathological alterations in the ventromedial prefrontal cortex (vmPFC) described in depression (MDD) might become even more pronounced over the course of illness. Measurement of brain metabolites by means of Magnetic Resonance spectroscopy (MRS) can indirectly deliver information about glial and neuronal integrity or potential cellular loss. The aim of this study was to investigate whether Glutamate (Glu), Choline (Cho) and total N-acetylaspartate (total-NAA) levels in the vmPFC differed among MDD patients in distinct stages of illness and healthy controls. We hypothesized that high-past illness-burden would represent more metabolite abnormalities independently of mood state. A 3-Tesla MR facility was used to measure these metabolites in vmPFC of 45 depressive patients (10 first-episode-MDD, 16 remitted-recurrent-MDD and 19 chronic-MDD) and 15 healthy controls. Multivariate and correlation analyses were carried out to explore the influence of duration of illness, age at onset and mood-state. Levels of Glu were significantly decreased in remitted-recurrent and chronic patients compared with both first-episode and controls (up to 28% mean reduction; p < 0.001, Cohen's d = 2.88) and were negatively correlated with illness duration (r = -0.56; p < 0.001). Cho levels showed an opposite pattern: highest values were detected in chronic patients, correlating positively with duration of illness (r = 0.32; p = 0.03). Total-NAA levels were significantly lowered in remitted-recurrent and chronic patients, which were associated with an earlier age at onset (r = 0.50; p = 0.001). Our data suggest that abnormalities in Glu, Cho and total-NAA levels are consistently related to the course of MDD, supporting the hypothesis that cellular changes would take place in vmPFC over time. [PubMed Citation] [Order full text from Infotrieve]

8) Zarate C, Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore G
Glutamatergic modulators: the future of treating mood disorders?
Harv Rev Psychiatry. 2010 Oct;18(5):293-303.
Mood disorders such as bipolar disorder and major depressive disorder are common, chronic, and recurrent conditions affecting millions of individuals worldwide. Existing antidepressants and mood stabilizers used to treat these disorders are insufficient for many. Patients continue to have low remission rates, delayed onset of action, residual subsyndromal symptoms, and relapses. New therapeutic agents able to exert faster and sustained antidepressant or mood-stabilizing effects are urgently needed to treat these disorders. In this context, the glutamatergic system has been implicated in the pathophysiology of mood disorders in unique clinical and neurobiological ways. In addition to evidence confirming the role of the glutamatergic modulators riluzole and ketamine as proof-of-concept agents in this system, trials with diverse glutamatergic modulators are under way. Overall, this system holds considerable promise for developing the next generation of novel therapeutics for the treatment of bipolar disorder and major depressive disorder. [PubMed Citation] [Order full text from Infotrieve]

9) Reynolds LM, Reynolds GP
Differential regional N-acetylaspartate deficits in postmortem brain in schizophrenia, bipolar disorder and major depressive disorder.
J Psychiatr Res. 2011 Jan;45(1):54-9.
There is substantial evidence for the involvement of the hippocampus and subcortical regions in the neuropathology of schizophrenia. Deficits of N-acetylaspartate (NAA) have been found in schizophrenia and bipolar disorder which may reflect neuronal loss and/or dysfunction. N-acetylaspartylglutamate (NAAG) is the most abundant peptide transmitter in the mammalian nervous system. It is an agonist at presynaptic metabotropic glutamate receptors mGluR3, inhibiting glutamate release. NAA and NAAG and were measured in hippocampal, striatal, amygdala and cingulate gyrus regions of human postmortem tissue from controls and subjects with schizophrenia, bipolar disorder and major depressive disorder. There are significant deficits in hippocampal NAA concentrations in all patient groups. In the amygdala there are significant NAA deficits in schizophrenia and depression and significant deficits of NAAG in the amygdala in the depression group. The deficits in NAA reported in this study confirm the importance of hippocampal and other subcortical structures in the neuropathology of the major psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

10) DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA
Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.
J Clin Psychiatry. 2010 Dec;71(12):1605-11.
[PubMed Citation] [Order full text from Infotrieve]

11) Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC
Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder.
NMR Biomed. 2010 Jul;23(6):643-50.
Chronic fatigue syndrome (CFS), a complex illness characterized by fatigue, impaired concentration, and musculoskeletal pain, is often misdiagnosed as a psychiatric illness due to the overlap of its symptoms with mood and anxiety disorders. Using proton magnetic resonance spectroscopic imaging ((1)H MRSI), we previously measured levels of the major brain metabolites in CFS, in generalized anxiety disorder (GAD), and in healthy control subjects, and found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in CFS compared to the other two groups. In the present study, we sought to assess the specificity of this observation for CFS by comparing ventricular lactate levels in a new cohort of 17 CFS subjects with those in 19 healthy volunteers and in 21 subjects with major depressive disorder (MDD), which, like GAD, is a neuropsychiatric disorder that has significant symptom overlap with CFS. Ventricular CSF lactate was significantly elevated in CFS compared to healthy volunteers, replicating the major result of our previous study. Ventricular lactate measures in MDD did not differ from those in either CFS or healthy volunteers. We found a significant correlation between ventricular CSF lactate and severity of mental fatigue that was specific to the CFS group. In an exploratory analysis, we did not find evidence for altered levels of the amino acid neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate + glutamine ('Glx'), in CFS compared to MDD or healthy controls. Future (1)H MRS studies with larger sample sizes and well-characterized populations will be necessary to further clarify the sensitivity and specificity of neurometabolic abnormalities in CFS and MDD. [PubMed Citation] [Order full text from Infotrieve]

12) Takahashi K, Murasawa H, Yamaguchi K, Yamada M, Nakatani A, Yoshida M, Iwai T, Inagaki M, Yamada M, Saitoh A
Riluzole rapidly attenuates hyperemotional responses in olfactory bulbectomized rats, an animal model of depression.
Behav Brain Res. 2011 Jan 1;216(1):46-52.
Growing evidence indicates that the glutamatergic neurotransmitter system is central to the neurobiology and treatment of depression. Riluzole, a drug currently used to slow the progression of amyotrophic lateral sclerosis (ALS), directly affects the glutamatergic system. In this study, we investigated the effects of riluzole in olfactory bulbectomy (OBX) rats, an animal model of depression. The olfactory bulbs in rats were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed significant increases in emotionality responses. Single (1st day administration) and subchronic (7th day administration) riluzole treatment (1-10 mg/kg, po) significantly and dose-dependently reduced hyperemotional responses in OBX rats. Both single and subchronic riluzole treatment (10 mg/kg, po) had no significant effects on the emotional responses in sham operated rats. In addition, we demonstrated that single riluzole treatment (10 mg/kg, po) significantly decreased extracellular glutamate levels in medial prefrontal cortex of OBX rats by in vivo microdialysis. We provide the first experimental evidence that riluzole rapidly attenuated hyperemotional responses in OBX rats, an animal model of depression. [PubMed Citation] [Order full text from Infotrieve]

13) Iyo AH, Feyissa AM, Chandran A, Austin MC, Regunathan S, Karolewicz B
Chronic corticosterone administration down-regulates metabotropic glutamate receptor 5 protein expression in the rat hippocampus.
Neuroscience. 2010 Sep 15;169(4):1567-74.
Several lines of evidence suggest a dysfunctional glutamate system in major depressive disorder (MDD). Recently, we reported reduced levels of metabotropic glutamate receptor subtype 5 (mGluR5) in postmortem brains in MDD, however the neurobiological mechanisms that induce these abnormalities are unclear. In the present study, we examined the effect of chronic corticosterone (CORT) administration on the expression of mGluR5 protein and mRNA in the rat frontal cortex and hippocampus. Rats were injected with CORT (40 mg/kg s.c.) or vehicled once daily for 21 days. The expression of mGluR5 protein and mRNA was assessed by Western blotting and quantitative real-time PCR (qPCR). In addition, mGluR1 protein was measured in the same animals. The results revealed that while there was a significant reduction (-27%, P=0.0006) in mGluR5 protein expression in the hippocampus from CORT treated rats, mRNA levels were unchanged. Also unchanged were mGluR5 mRNA and protein levels in the frontal cortex and mGluR1 protein levels in both brain regions. Our findings provide the first evidence that chronic CORT exposure regulates the expression of mGluR5 and are in line with previous postmortem and imaging studies showing reduced mGluR5 in MDD. Our findings suggest that elevated levels of glucocorticoids may contribute to impairments in glutamate neurotransmission in MDD. [PubMed Citation] [Order full text from Infotrieve]

14) Miguel-Hidalgo JJ, Waltzer R, Whittom AA, Austin MC, Rajkowska G, Stockmeier CA
Glial and glutamatergic markers in depression, alcoholism, and their comorbidity.
J Affect Disord. 2010 Dec;127(1-3):230-40.
[PubMed Citation] [Order full text from Infotrieve]

15) Numakawa T, Kunugi H
[Possible interaction between glucocorticoid and BDNF function].
Seikagaku. 2010 May;82(5):419-22.
[PubMed Citation] [Order full text from Infotrieve]

16) Elizalde N, Pastor PM, Garcia-García AL, Serres F, Venzala E, Huarte J, Ramírez MJ, Del Rio J, Sharp T, Tordera RM
Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1.
J Neurochem. 2010 Sep 1;114(5):1302-14.
Depression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein vesicular glutamate transporter 1 (VGLUT1), have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that chronic mild stress induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein - Arc) but a long-lasting decrease of the brain derived neurotrophic factor as well as depressive-like behaviour. The immediate early gene Arc was also down-regulated in VGLUT1+/- heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressive-like behaviour both in animal models and in depressed patients. [PubMed Citation] [Order full text from Infotrieve]

17) Salustri C, Squitti R, Zappasodi F, Ventriglia M, Bevacqua MG, Fontana M, Tecchio F
Oxidative stress and brain glutamate-mediated excitability in depressed patients.
J Affect Disord. 2010 Dec;127(1-3):321-5.
[PubMed Citation] [Order full text from Infotrieve]

18) Murrough JW, Henry S, Hu J, Gallezot JD, Planeta-Wilson B, Neumaier JF, Neumeister A
Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder.
Psychopharmacology (Berl). 2011 Feb;213(2-3):547-53.
[PubMed Citation] [Order full text from Infotrieve]

19) Elizalde N, García-García AL, Totterdell S, Gendive N, Venzala E, Ramirez MJ, Del Rio J, Tordera RM
Sustained stress-induced changes in mice as a model for chronic depression.
Psychopharmacology (Berl). 2010 Jun;210(3):393-406.
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20) Wolkowitz OM, Epel ES, Reus VI, Mellon SH
Depression gets old fast: do stress and depression accelerate cell aging?
Depress Anxiety. 2010 Apr;27(4):327-38.
Depression has been likened to a state of "accelerated aging," and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress-related depression may contribute to "accelerated aging," cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic-pituitary-adrenal axis (e.g., hyper- or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain-derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re-conceptualization of depression as a whole body disease rather than just a "mental illness," and to the rational development of new classes of medications to treat depression and its related medical comorbidities. [PubMed Citation] [Order full text from Infotrieve]