Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine

Abstract

Background:Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression.Methods:We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor, TrkB, phospho-TrkB, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1), postsynaptic density protein 95, and dendritic spine density in selected brain regions were measured.Results:In the tail suspension and forced swimming tests, both MGS0039 and ketamine significantly attenuated the increased immobility time observed in susceptible mice, compared with vehicle-treated animals, 1 or 2 days after a single dose of drug. In the sucrose preference test, both compounds significantly improved the reduced preference typically seen in susceptible mice at 3 to 7 days after a single dose of drug. Western-blot analyses showed that similar to ketamine, MGS0039 significantly attenuated the reduced brain-derived neurotrophic factor, phospho-TrkB/TrkB ratio, GluA1 and postsynaptic density protein 95 seen in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from susceptible mice, 8 days after a single dose. Again, in a similar manner to ketamine, MGS0039 significantly attenuated the reduction of spine density in the prelimbic regions of the medial prefrontal cortex, dentate gyrus, and CA3 of the hippocampus, but not infralimbic regions of the medial prefrontal cortex and CA1, in susceptible mice 8 days after a single dose. In contrast, neither drug elicited an effect on altered brain-derived neurotrophic factor-TrkB signaling, GluA1, and postsynaptic density protein 95 levels and did not increase spine density observed in the nucleus accumbens of susceptible mice.Conclusions:Similar to ketamine, MGS0039 shows rapid and sustained antidepressant effects in the social defeat stress model. Long-lasting synaptogenesis in the prelimbic regions of medial prefrontal cortex, dentate gyrus, and CA3 might be implicated in this sustained antidepressant effect.

Brain-derived neurotrophic factor-TrkB signaling in the medial prefrontal cortex plays a role in the anhedonia-like phenotype after spared nerve injury

“…Low levels of BDNF in the mPFC are associated with the development of depression-like phenotypes including anhedonia in rodents [19][20][21][22][23][24][25][26][27][28]41]. In contrast, we found increased BDNF-TrkB signaling in the NAc from rats with anhedonialike phenotypes, consistent with the previous reports from rodents with depression-like phenotypes [19][20][21][22][23][24][25][26][27][28].…”

“…Low levels of BDNF in the mPFC are associated with the development of depression-like phenotypes including anhedonia in rodents [19][20][21][22][23][24][25][26][27][28]41]. In contrast, we found increased BDNF-TrkB signaling in the NAc from rats with anhedonialike phenotypes, consistent with the previous reports from rodents with depression-like phenotypes [19][20][21][22][23][24][25][26][27][28]. Interestingly, ANA-12 did not improve the decreased sucrose preference of rats with anhedonia-like phenotypes, although ANA-12 significantly attenuated increased BDNF-TrkB signaling in the NAc from rats with anhedonia-like phenotypes.…”

“…Decreased BDNF-TrkB signaling in the prefrontal cortex (PFC) and hippocampus was shown in conditions of chronic unpredictable mild stress (CUMS) [19], inflammation [20][21][22], chronic social defeat stress (CSDS) [23][24][25], and learned helplessness (LH) [26,27]. In contrast, increased BDNF-TrkB signaling in the nucleus accumbens (NAc) was detected in inflammation [20,21], CSDS [23][24][25], and LH models [26,27]. Recent studies suggest that regional differences in BDNF-TrkB signaling confer resilience to inescapable stress [27,28].…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…In particular, a single administration of an mGluR 2/3 antagonist reduced immobility time in the 24-h forced-swim test [193], decreased time delay until food consumption in the novelty-suppressed feeding test [194, 195], rapidly reversed chronic stress-induced decreases in sucrose preference - which was sustained for at least 10 days - [196] and reversed chronic corticosterone-induced behavioral deficits [197] in rodents (see Table 1). In addition, mGluR 2/3 blockade reversed the decrease in sucrose preference produced by chronic social defeat stress in mice [198]. While a large (N= 310 patients) clinical trial of a negative allosteric modulator of mGluR 2 (RG1578; decoglurant) failed to demonstrate antidepressant responses compared to placebo [see abstract: 199] (see Table 2), no measure of target engagement was included in this trial and therefore additional studies are needed to determine the potential of mGluR 2/3 antagonists in the treatment of treatment-resistant depression.…”

“…Likewise, the mGluR 2/3 antagonist MGS0039 also reverses chronic-stress-induced decreases in spine density in the prelimbic area of the mPFC and hippocampus of mice [198]. GLYX-13 also rapidly increases spine number and function in layer 5 neurons of the mPFC [128].…”