On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039

Abstract

Rationale: Several studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear.

Objectives: The aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated.

Results: The results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound.

Conclusions: The results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs.

Fig. 1

The effect of amitriptyline (AMI; 10 mg/kg, IP) and MGS0039 (1 and 3 mg/kg, IP) on the ambulatory movement (a) and the number of rearings (b) in the OB model of depression. Rats were administrated for 14 days with each compound in each group. At 24 h following the last treatment, ambulatory scores were measured in the “open field”. Data from the session is expressed as mean and SEM and analyzed using two-way ANOVA followed by the Fisher LSD test. #p < 0.00001 vs. sham/vehicle group; *p < 0.001, **p < 0.0001 vs. OB/vehicle group. Six to seven animals per group were used

Fig. 2

The effect of amitriptyline (AMI; 10 mg/kg, IP) and MGS0039 (1 and 3 mg/kg, IP) in the passive avoidance paradigm in the OB model of depression. Rats were administrated for 14 days with each compound in each group. At 24 h following the last treatment, the number of scores was measured in the passive avoidance paradigm. Data from the session is expressed as mean and SEM and analyzed using two-way ANOVA followed by the Fisher LSD test. #p < 0.00001 vs. sham/vehicle group; *p < 0.00001 vs. OB control group. Seven animals per group were used

Fig. 3

a The effect of WAY100635 (0.1 mg/kg) on the antidepressant-like activity of MGS0039 (3 mg/kg) in the TST in mice. Mice were pretreated with WAY100635 and with MGS0039, respectively, 45 and 30 min before the test. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test, ***p < 0.001 vs. control group. b The effect of WAY100635 (0.1 mg/kg) on the antidepressant-like activity of MGS0039 (0.3 mg/kg) in the TST in mice. Mice were pretreated with WAY100635 and with MGS0039, respectively, 45 and 30 min before the test. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test. c The effect of ritanserin (0.5 mg/kg) on the antidepressant-like activity of MGS0039 (3 mg/kg) in the TST in mice. Mice were pretreated with ritanserin and with MGS0039, respectively, 60 and 30 min before the test. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test, ***p < 0.001 vs. control group. Seven animals per group were used

Fig. 4

The effect of WAY100635 (0.1 mg/kg) (Fig. 2a), ritanserin (0.5 mg/kg) (Fig. 2b), or metergoline (0.5 mg/kg) (Fig. 2c) on the antidepressant-like activity of LY341495 (1 mg/kg) in the TST in mice. WAY100635 was given 45 min, ritanserin 60 min, metergoline 60 min, and LY341495 30 min before the test. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test, ***p < 0.001 vs. control group. Seven to eight animals per group were used

Fig. 5

The effect of NBQX (10 mg/kg) on the antidepressant-like activity of MGS0039 (3 mg/kg) in the TST in mice. NBQX and MGS0039 were given, respectively, 35 and 30 min before the test. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test. ***p < 0.001 vs. control group, #p < 0.05 vs. MGS0039-treated group. Seven animals per group were used

Fig. 6

The effects of serotonin depletion on the antidepressant-like activity of citalopram (Fig. 7a) or MGS0039 (Fig. 7b) in the TST in mice. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test. ***p < 0.001 vs. vehicle + vehicle-treated group, ##p < 0.001 vs. MGS0039-treated group. Seven to eight animals per group were used

Fig. 7

The effects of AMPA receptor antagonist, NBQX (10 mg/kg) (Fig. 8a) or NBQX (20 mg/kg) (Fig. 8b) on the antidepressant-like activity of MGS0039 (3 mg/kg) in serotonin-depleted mice in the TST. Values are expressed as the means ± SEM and analyzed by two-way ANOVA followed by Bonferroni's post hoc test. ***p < 0.001 vs. vehicle + vehicle-treated group, #p < 0.05 vs. MGS0039-treated group. Seven to eight animals per group were used

Fig. 8

a The effect of WAY100635 (0.1 mg/kg) on the locomotor activity of MGS0039 (3 mg/kg) in mice. WAY100635 and MGS0039 were administered, respectively, 45 and 30 min before the test. Values expressed as the means ± SEM were evaluated by repeated measure ANOVA. **p < 0.01 vs. WAY100635-treated group and ***p < 0.001 vs. control group (Dunnett's test). b The effect of WAY100635 (0.1 mg/kg) on the locomotor activity of MGS0039 (0.3 mg/kg) in mice. WAY100635 and MGS0039 were administered, respectively, 45 and 30 min before the test. Values expressed as the means ± SEM were evaluated by repeated measure ANOVA. c The effect of ritanserin (0.5 mg/kg) on the locomotor activity of MGS0039 (3 mg/kg) in mice. Ritanserin and MGS0039 were administered, respectively, 60 and 30 min before the test. Values expressed as the means ± SEM were evaluated by repeated measure ANOVA. *p < 0.05 vs. ritanserin-treated group and **p < 0.01 vs. control group (Dunnett's test). d The effect of NBQX (10 mg/kg) on the locomotor activity of MGS0039 (3 mg/kg) in mice. NBQX and MGS0039 were administered, respectively, 35 and 30 min before the test. Values expressed as the means ± SEM were evaluated by repeated measure ANOVA. Six animals per group were used

Fig. 9

The effects of citalopram (a) and MGS0039 (b) on the locomotor activity of serotonin-depleted and control mice. Values expressed as the means ± SEM were evaluated by repeated measure ANOVA, **p < 0.01 vs. respective control group (Dunnett's test). Seven animals per group were used