A novel mGlu4 selective agonist LSP4-2022 increases behavioral despair in mouse models of antidepressant action

Numerous data have indicated that metabotropic glutamate (mGlu) receptor ligands may be potentially useful as novel antidepressant drugs (ADs). The Group III mGlu receptor has not been explored much because of the limited access to selective ligands, but some behavioral studies have indicated that modulating group III mGlu receptors may result in benefits for the therapy of depression. Here, we investigated the potential antidepressant-like effects of a new mGlu4 selective orthosteric agonist, LSP4-2022. We found that the drug induced pro-depressant effects in the tail suspension test (TST) and the forced swim test (FST) in mice at doses that did not change the locomotor activity of the animals. Additional experiments that used knock-out (KO) mice and aimed to verify the selectivity of LSP4-2022 revealed that the drug induced strong pro-depressant-like effects in mGlu7 KO mice but did not affect the behavior of mGlu4 KO mice in the TST, suggesting that the activation of the mGlu4 receptor plays a role in producing the pro-depressant activity of the tested drug. The results of our study indicate that the inhibition rather than activation of mGlu4 receptors might induce antidepressant effects, but this hypothesis should be verified using a selective mGlu4 receptor antagonist, which is currently not available.