Glutamate and Depression

Abstract

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.

Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test

“…Additionally, the decrease of glutamate release by lamotrigine might be result of the blockade of pre-synaptic voltage-dependent sodium and calcium channels [46]. Our results corroborate previous experiments, demonstrating the involvement of NMDA receptors in the pathophysiology of depression [26,63]. We showed that anti-depressant like effect of lamotrigine was boosted by using different types of NMDA receptor antagonists, supporting the implication of NMDA in antidepressant-like effect of lamotrigine.…”

“…For example, blockade of NMDA receptors exerts antidepressant-like response [72]. Similarly, antidepressant agents diminish the function, activation, binding capacity and expression of NMDA receptors [11,62,63]. Surprisingly, only a small number of experiments reported the interaction of lamotrigine with NMDA receptors.…”

Neurochemistry of the Nucleus Accumbens and its Relevance to Depression and Antidepressant Action in Rodents

“…Dysfunction of excitatory amino acid transmission may play a role in the etiology and pathophysiology of depression [121]. In clinical studies, it has been reported that elevated glutamate levels were observed in plasma and cerebrospinal fluid of depressed patients [4,87,98], and the administration of antidepressants has been shown to decrease plasma glutamate levels significantly in patients diagnosed with depression [89].…”

Psychotherapeutic Benefits of Opioid Agonist Therapy

“…The NMDA system also plays a major role in mood regulation, specifically modulating depression and anxiety. 43,44 When activated by glutamate, NMDA receptors located on serotonin neurons exact distinct "anti-serotonin" effects and inhibite serotonin synthesis and release and increase serotonin degradation. All of these factors contribute to depression and anxiety.…”

“…43,44 Lamotrignine (Lamictal) decreases brain glutamate production, which decreases neuronal excitability, and is approved for the management of bipolar disorder and seizure disorders. 12 In an animal model, lamotrignine demonstrated a potent anxyolytic effect by decreasing the subjects' brain glutamate.…”