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. 2017 Mar 7;4(1):ENEURO.0285-16.2017.
doi: 10.1523/ENEURO.0285-16.2017. eCollection Jan-Feb 2017.

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

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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 et al. eNeuro. .
Free PMC article

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.

Keywords: GABA-NAM; antidepressant; behavior; depression; ketamine; γ oscillation.

Figures

Figure 1.
Figure 1.
Antidepressant effects of MRK-016 in the forced-swim and FUST. A, Mice received intraperitoneal injections of vehicle (VEH), ketamine (KET) or MRK-016 and were tested in the FST 1 h posttreatment. Acute administration of KET (n = 10) and MRK-016 (n = 10) significantly reduced immobility in the FST compared with VEH-treated (n = 10) mice; one-way ANOVA followed by Holm-Šídák multiple comparison. B, Unstressed control mice displayed no significant change in preference for female urine in two repeated baseline tests or after acute administration of vehicle or MRK-801. C, To investigate MRK-016’s antianhedonic properties, male mice that lost their preference for sniffing female urine following a 10-d restraint stress protocol received VEH (n = 10), fluoxetine (FLX; n = 9), KET (n = 9), or MRK-016 (n = 9) and were retested in the FUST 48 h later. Administration of KET and MRK-016 reversed the anhedonia phenotype; two-way repeated measures ANOVA followed by Holm-Šídák post hoc test. Data are the mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 2.
Figure 2.
NBQX administration prevents MRK-016 -induced oscillatory EEG activity in vivo. Administration of MRK-016 increased γ (A, B) and α (C) oscillations in vivo after prior injection of saline but not after prior injection of NBQX. MRK-016 had no significant effect on β, δ, or θ activity under either condition. Two-way repeated measures ANOVA followed by Holm-Šídák post hoc test (vehicle: n = 8; MRK-016: n = 9). Data are the mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 versus baseline; #p < 0.05, ##p < 0.01 versus vehicle.
Figure 3.
Figure 3.
Preadministration of the AMPAR antagonist NBQX prevented the antidepressant effects of MRK-016. NBQX pretreatment 10 min before drug injection prevented the antidepressant-like effects of MRK-016 in the FST as determined 1 h postinjection and 24 h postinjection; two-way ANOVA followed by Holm-Šídák post hoc test (SAL/VEH: n = 7; SAL/MRK-016: n = 7; NBQX/VEH: n = 7; NBQX/MRK-016: n = 7). Data are the mean ± SEM. *p < 0.05, **p < 0.01.
Figure 4.
Figure 4.
Administration of DMSO does not alter baseline behavioral outcomes in mice. Administration of DMSO did not alter (A) locomotor activity (n = 9/group), (B) immobility time in the FST (n = 10/group), (C) PPI (n = 17/group), (D) startle amplitude (n = 17/group), or (E) motor coordination (SAL: n = 8; DMSO: n = 9) compared with saline-treated mice. Data are the mean ± SEM.
Figure 5.
Figure 5.
Administration of MRK-016 does not elicit ketamine-like side effects. A, After recording baseline activity for 1 h, mice received drug (marked by a vertical dashed line), and locomotor activity was monitored for another 1 h. Administration of ketamine increased locomotor activity, while administration of vehicle or MRK-016 at two doses did not. B, Unlike ketamine, MRK-016 did not disrupt motor coordination of mice in the rota-rod test; two-way repeated measures ANOVA followed by Holm-Šídák post hoc test; (n = 9/treatment group). C, Ketamine treatment induced a place preference, revealed as an increased time spent in the drug-paired compartment during the postconditioning (Post-Cond) phase compared with preconditioning (Pre-Cond). However, MRK-016 did not elicit any conditioning in the CPP paradigm; two-way repeated measures ANOVA followed by Holm-Šídák post hoc test; (n = 10/treatment group). D, Administration of ketamine (n = 7; 30 mg/kg) was associated with a disruption of %PPI, whereas MRK-016 at 3 mg/kg (n = 7) or 9 mg/kg (n = 8) did not affect %PPI compared with control (n = 6); two-way repeated measures ANOVA followed by Holm-Šídák post hoc test. Data are the mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

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