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.

Keywords: BDNF-TrkB signaling; antidepressant; ketamine; metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist; social defeat stress model; synaptogenesis.

Figure 1.

Schedule of social defeat stress, treatment, and behavioral tests. a: The schedule of social defeat stress (10 days), drug treatment, and behavioral tests. Social defeat stress was performed from day 1 to day 10. Social interaction test was performed on day 11. Vehicle (10 mL/kg), MGS0039 (1 mg/kg), or ketamine (10 mg/kg) was administered i.p into susceptible mice on day 12. Locomotion test (LMT), tail suspension test (TST), and forced swim test (FST) were performed 0.5, 24, and 48 hours after a single injection, respectively. A 1% sucrose preference test (SPT) was performed 3 day (day 15) and 7 days (day 19) after a single injection. (b) The schedule of social defeat stress (10 days), drug treatment, and collection brain samples for western blot. Social interaction test was performed on day 11. Vehicle (10 mL/kg), MGS0039 (1 mg/kg), or ketamine (10 mg/kg) was administered i.p into susceptible mice on day 12. Brain samples were collected on day 20. (c) The schedule of social defeat stress (10 days), drug treatment, and collection brain samples for Golgi staining. Social interaction test was performed on day 11. Vehicle (10 mL/kg), MGS0039 (1 mg/kg), or ketamine (10 mg/kg) was administered i.p into susceptible mice on day 12. Brain samples were collected on day 20. Ket, ketamine; MGS, MGS0039; Veh, vehicle.

Figure 2.

Antidepressant effects of MGS0039 and ketamine in the social defeat mice. (a) Locomotion test (LMT). (b) Tail suspension test (TST). (c) forced swim test (FST). (d-e) 1% sucrose preference test (SPT). The values represent the mean ± SEM (n = 9). *P < .05, **P < .01, ***P < .001 compared with the vehicle + stress group. Ket, ketamine; MGS, MGS0039; Veh, vehicle.

Figure 3.

Effects of MGS0039 and ketamine on the brain-derived neurotrophic factor (BDNF) and TrkB phosphorylation in the brain regions. (a) Expression of BDNF in the brain regions. (b) Ratio of phosphorylated TrkB (p-TrkB) to total TrkB in the brain regions. (c) Expression of GluA1 in the brain regions. (d) Expression of postsynaptic density protein 95 (PSD95) in the brain regions. The value was expressed as a percentage of that of control mice. The values represent the mean ± SEM (n = 5 or 6). *P < .05, **P < .01, ***P < .001 compared with the vehicle + stress group. Ket, ketamine; MGS, MGS0039; Veh, vehicle.

Figure 4.

Effects of MGS0039 and ketamine on alterations in dendritic spine density in the brain regions after social defeat stress. (a) Prelimbic region (PrL) of medial prefrontal cortex (mPFC). (b) Infralimbic region (IL) of mPFC. (c) nucleus Accumbens (NAc) core. (d) NAc shell. (e) Dentate gyrus (DG). (f) CA1. (g) CA3. Scale bar = 10 μm. Values represent the mean ± SEM (n = 6). Representative photomicrographs of Golgi-Cox stained pyramidal neurons in the selected brain regions from animals of each group. ***P < .001 compared with the vehicle + stress group. Ket, ketamine; MGS, MGS0039; Veh, vehicle.