Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems.

Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT(2A/C) receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111.