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
eNeuro 2017 DOI: 10.1523/eneuro.0285-16.2017 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male mice; female mice in the chronic stress anhedonia test |
| Interventions | MRK-016 NBQX |
| Measures | forced swim test, female urine sniffing test (FUST), electroencephalogram (EEG) gamma power, rota-rod performance, prepulse inhibition (PPI), conditioned place preference (CPP), locomotion |
| Topics | Esketamine Ketamine |
| Citations | 109 |
| Key points | The α5 GABA-NAM MRK-016 produced rapid antidepressant-like effects in the forced swim test at 1 and 24 hours and an anti-anhedonic effect after chronic stress, resembling ketamine's rapid actions. These effects, along with a transient increase in EEG gamma power, were blocked by the AMPA receptor antagonist NBQX. Unlike ketamine, MRK-016 caused no motor impairment, prepulse inhibition reduction, conditioned place preference, or locomotion change, which the authors propose makes α5 GABA-NAMs promising fast-acting antidepressants with fewer side effects. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 24
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide F1000Research May 24, 2018
and 19 more in the library
Cites 10
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine use: a review Addiction July 21, 2011
- Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study Biological Psychiatry November 4, 2015
and 5 more in the library