A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice.
Panos Zanos,Mackenzie E. Nelson,Jaclyn N. Highland,Samuel R. Krimmel,Polymnia Georgiou,Todd D. Gould,Scott M. Thompson +6 more
- Vol. 4, Iss: 1
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TLDR
This article showed that negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses.Abstract:
New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.read more
Citations
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Mechanisms of ketamine action as an antidepressant.
Panos Zanos,Todd D. Gould +1 more
TL;DR: In this article, the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of α-amino-3-hydroxy-5methyl-4-isoxazole-propionic acid receptor activation.
Journal ArticleDOI
Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments
TL;DR: These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients.
Journal ArticleDOI
Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective.
TL;DR: The author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamines and discusses the other potential rapid‐acting antidepressant candidates to compare them with ketamine.
Journal ArticleDOI
Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions
TL;DR: It is concluded that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders.
Journal ArticleDOI
The future of rodent models in depression research.
TL;DR: This Review examines the importance of sex as a biological variable and the controversial idea of intergenerational and transgenerational transmission of depressive-like traits, and discusses how genetic and circuit-dissection techniques might be used to refine existing models and generate new ones.
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