AMPA Receptor Potentiators as Novel Antidepressants

Alt, Andrew; Witkin, J M; Bleakman, David

doi:10.2174/1381612053764814

Cited by 54 publications

(24 citation statements)

References 135 publications

(206 reference statements)

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“…These compounds (so-called AMPA receptor-positive modulators or AMPA receptor potentiators, ARPs) do not activate AMPA receptors themselves, but slow the rate of receptor desensitization and/or deactivation in the presence of an agonist (eg, glutamate and AMPA). Studies have shown that the biarylpropylsulfonamide ARPs (LY392098 and LY451616) have antidepressant effects in animal models of depression (including the application of inescapable stressors, forced-swim test, and tail-suspension-induced immobility tests), in learned-helplessness models of depression, and in animals exposed to chronic mild stress procedure (Alt et al, 2005;Li et al, 2001), Moreover, Ampalex was reported to have more rapid effect (during the first week of treatment) than fluoxetine (after 2 weeks) (Knapp et al, 2002). It is note worthy that lamotrigine has been shown to have an antidepressant effect in forced-swim test animal models (Szymczyk and Zebrowska-Lupina, 2000).…”

Section: Ampa Receptors and Affective-like Behaviormentioning

confidence: 99%

The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

Suzuki

Wei

et al. 2006

Neuropsychopharmacol

192

153

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A growing body of data suggests that the glutamatergic system may be involved in the pathophysiology and treatment of severe mood disorders. Chronic treatment with the antimanic agents, lithium and valproate, resulted in reduced synaptic expression of the AMPA(-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit GluR1 in the hippocampus, while treatment with an antidepressant (imipramine) enhanced the synaptic expression of GluR1. The anticonvulsants, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) and riluzole (2-amino-6-trifluoromethoxybenzothiazole), have been demonstrated to have efficacy in the depressive phase of bipolar disorder. We therefore sought to determine the role of these anticonvulsants, compared to that of the predominantly antimanic anticonvulsant valproate, on AMPA receptor localization. We found that the agents with a predominantly antidepressant profile, namely lamotrigine and riluzole, significantly enhanced the surface expression of GluR1 and GluR2 in a time-and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic agent, valproate, significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine-and riluzole-treated neurons, supporting the surface receptor changes. Phosphorylation of GluR1 at the PKA (cAMP-dependent protein kinase) site (S845) was enhanced in both lamotrigine-and riluzoletreated hippocampal neurons, but reduced in valproate-treated neurons. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, also increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Our findings suggest that regulation of GluR1/2 surface levels and function may be responsible for the different clinical profile of anticonvulsants (antimanic or antidepressant), and may suggest avenues for the development of novel therapeutics for these illnesses.

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Section: Ampa Receptors and Affective-like Behaviormentioning

confidence: 99%

The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

Suzuki

Wei

et al. 2006

Neuropsychopharmacol

192

153

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Section: Targeting Amparsmentioning

confidence: 99%

“…GluR1 phosphorylation is transiently increased by stress, possibly contributing to the stress-induced facilitation of memory [122] . In addition, the AMPAR potentiators LY392098 and LY451646 have antidepressant effects in the FST and TST [123][124][125] .Enhanced phosphorylation of GluR1 has been detected following fluoxetine, imipramine, and ketamine treatment, and ketamine rapidly increases postsynaptic AMPAR expression [103,104,115] . Moreover, the onset of ketamine effects requires AMPARs, as the antidepressant-like behaviors are attenuated by pre-treatment with the AMPAR antagonist NBQX in mouse models of depression [116] .…”

mentioning

confidence: 99%

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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“…The antidepressant fluoxetine positively modulate AMPA receptors 26) . Positive AMPA receptor modulators (potentiators) produced antidepressant-like effects in the FST and tail suspension test (TST) 27) . Moreover, 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(ƒ)quinoxaline (NBQX), an AMPA receptor antagonist, has been found to block the antidepressant-like effect of the NMDA receptor an-SS Hong, SH Cho 283 tagonists 28,29) , which suggests that this effect may be mediated by an increased AMPA-to-NMDA receptor throughput in neuronal circuits 28) .…”

Section: Introductionmentioning

confidence: 99%

Antidepressant-like Effects of the Gastrodia elata Bl Extract in Mice

Hong¹,

Cho²

2013

Journal of Oriental Neuropsychiatry

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Objectives :A growing body of evidence has suggested that the dysfunction of glutamatergic systems plays a pivotal role in major depressive disorder (MDD). This study was performed to investigate the antidepressant-like effects of the ethanolic extract of Gastrodia elata Bl (GE) in mouse models and to investigate the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in producing these antidepressant-like effects. Methods :The forced swim test (FST) and tail suspension test (TST) were used to investigate GE's behavioral effects in mice. Additional biochemical and behavioral experiments with NBQX, an AMPA receptor antagonist, were undertaken to determine whether the antidepressant-like properties of GE are involved in AMPA receptor throughput. Results :Oral administration of GE extract (1,600 mg/kg) 1h prior to testing significantly reduced the immobility times in the FST and TST. These antidepressant-like effects of GE extract were increased dose-dependently. Pre-treatment with NBQX significantly attenuated the reduction in immobility time induced by the GE extract in the FST and TST. Conclusions :The ethanolic extract of GE may exert antidepressant-like effects with involvement of AMPA receptor.

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AMPA Receptor Potentiators as Novel Antidepressants

Cited by 54 publications

References 135 publications

The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Antidepressant-like Effects of the Gastrodia elata Bl Extract in Mice

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