A selective mGlu7 receptor antagonist MMPIP reversed antidepressant-like effects of AMN082 in rats

Previous behavioural studies strongly indicated on potential antidepressant-like activity of mGlu7 positive allosteric modulator, AMN082 (N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride). However, the mechanism of action of this drug was not clear. Some recent data, showing possible off-target activities of AMN082 and its metabolites casted doubt on the role of mGlu7 receptor activation in the antidepressant-like activity of this compound. In the present study we used a selective mGlu7 receptor antagonist, MMPIP (6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one), to investigate the role of mGlu7 receptor blockade in the antidepressant action of AMN082 in the forced swim test (FST) in rats. We showed that MMPIP (10 mg/kg, i.p.) completely reversed AMN082 (8 mg/kg, i.p.)-induced behavioural effects, including decreased immobility time and increased swimming time, suggesting the crucial role of mGlu7 receptor activation in the antidepressant-like effects of AMN082 in the FST. On the other hand, our studies showed, that AMN082 (8 mg/kg, i.p.)-induced decrease in locomotor activity was not affected by MMPIP (10 mg/kg, i.p.), indicating on other, non-mGlu7 receptor-dependent mechanisms involved in changes in locomotor activity of rats after AMN082 administration.

► MMPIP did not induce antidepressant-like effects in the forced swim test in rats. ► MMPIP reversed antidepressant-like effects of AMN082 in rats. ► AMN082-induced decrease in locomotor activity of rats was not affected by MMPIP.