Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

Trullás, Ramón; Skolnick, Phil

doi:10.1016/0014-2999(90)90204-j

Cited by 705 publications

(322 citation statements)

References 41 publications

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“…Glutamate receptor antagonists have been shown to have antidepressant activity in animal experiments (77)(78)(79) and in treatment-resistant MD (72,(80)(81)(82), and glutamate receptors are expressed in rodent vPAG (83).…”

Section: Discussionmentioning

confidence: 99%

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

Wang

Barde

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects.dorsal raphe | neuropeptide | siRNA | stress | transmitter coexistence T he indoleamine hypothesis of depression was formulated some five decades ago (1, 2), in parallel with the catecholamine hypothesis (3, 4), and has been supported by the success of selective serotonin reuptake inhibitors (SSRIs) for treatment of major depression (MD) (5). However, in a considerable number of cases, SSRIs are associated with side effects or lack of efficacy. For example, after treatment with SSRIs, only one-third of patients obtain full remission of symptoms (6). Therefore, there is an ongoing search for new medications targeting mood disorders, such as MD and anxiety. Here, neuropeptides and their receptors, the most diverse family of neurotransmitters in the brain (7), have been extensively explored (5,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), including galanin and its three receptors.Galanin is a 29-aa (30-aa in humans) neuropeptide (18) with a wide distribution in the rat brain (19,20), where it is coexpressed with noradrenaline/norepinephrine (NA) in locus coeruleus (LC) neurons and with 5-hydroxytryptamine (5-HT) in dorsal raphe nucleus (DR) neurons (21-25). There are three galanin receptors, GALR1-GALR3, which all belong to the family of seven transmembrane-spanning, G protein-coupled receptors (26-29). They are found in many areas of the rat brain, as first shown with autoradiographic ligand-binding methodology (30, 31), and later with in situ hybridization (ISH)/quantitative real-time PCR (qPCR) (32-36). The galanin system has been associated with numerous physiological and pathophysiological functions (29), including depression-and anxiety-like behaviors.There is early evidence from studies on the rat that central administration of galanin influences mood-related behavior in a region-specific way (37, 38), and also that galanin is prodepres...

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Section: Discussionmentioning

confidence: 99%

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

Wang

Barde

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…12,24,80,[93][94][95][96][97][98][99] Berman et al 93 studied seven subjects with major depression who, in a double-blind placebocontrolled manner, received intravenous ketamine or saline with active and sham treatments separated by at least 1 week. They noted a significant reduction in Hamilton Depression Rating Scale scores within 72 h after ketamine but not placebo, with results lasting for nearly 1 week.…”

Section: Antidepressant Effects On Glutamatergic Neurotransmissionmentioning

confidence: 99%

Advances in the treatment of anxiety: Targeting glutamate

Simon

Gorman

2006

NeuroRX

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Our current psychopharmacological treatments for anxiety disorders evince a number of shortcomings, including troublesome side effects and lack of primary effects. Whereas many new drugs have been developed in the past few decades, most are based on outmoded theories of the pathogenesis of these disorders (i.e., monoamine hypotheses), thus frustrating our ability to create more specific and effective interventions. Recently, however, the neurobiological literature has shown a convergence of findings focusing on the glutamatergic system in anxiety disorders, and the growth of pharmacological tools targeting these receptors has led to the development of novel treatments having anxiolytic effects in humans and animals alike. Additionally, as this system is showing promise as a final common pathway in the pathogenesis of anxiety disorders, we may be able to employ glutamate-specific neuroimaging techniques (e.g., N-acetyl-aspartate, GLX) to both guide treatment decisions and present reliable objective biomarkers for treatment efficacy.

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“…34,47 Both competitive and non-competitive NMDA receptor antagonists are active in the forced swimming test [77][78][79] and the learned helplessness model. 80 However, the relationship between NMDA blockade and antidepressant action is not clear-cut; in certain cases NMDA receptor antagonists can inhibit the action of clinically effective antidepressant treatments.…”

Section: Antidepressant Action Of Nmda-receptor-directed Compoundsmentioning

confidence: 99%

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission

Stewart

Reid

2002

Mol Psychiatry

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Specific targeting of the serotonergic and noradrenergic systems for the development of antidepressant compounds has resulted in drugs with more favourable side-effect profiles but essentially no greater efficacy than those compounds discovered more than 40 years ago. Alternative targets are now being considered in the hope that they will have a faster onset of action and be useful for those patients currently unresponsive to conventional treatments. Excitatory amino acid neurotransmission has been attributed various roles in both normal and abnormal brain function. The N-methyl-D-aspartate receptor in particular has long been postulated to play a role in the formation of memories. Major depressive disorder is characterised by alterations in cognitive function, as well as affect. Although there is evidence that early adverse events and stress can have a causal influence on depression, the underlying neurobiology of the disorder is poorly understood. This review will document current evidence for the involvement of excitatory amino acid neurotransmission in the pathophysiology of the affective disorders. The preclinical literature suggests that both electroconvulsive stimulation and antidepressant drugs can affect hippocampal long-term potentiation and the expression of excitatory amino acid receptor subtypes. Exposing animals to stress, including the kind that produces learned helplessness, can also affect synaptic plasticity in the hippocampus. There is clinical evidence that patients with chronic depression have structural brain abnormalities, including hippocampal atrophy, and a preliminary study has shown that an N-methyl-D-aspartate receptor antagonist may have antidepressant efficacy. Molecular Psychiatry (2002) 7, S15-S22.

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Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

Cited by 705 publications

References 41 publications

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

Advances in the treatment of anxiety: Targeting glutamate

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission

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