Mutual activation of glutamatergic mGlu(4) and muscarinic M(4) receptors reverses schizophrenia-related changes in rodents

RATIONALE: Metabotropic glutamate receptors and muscarinic M(4) receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to G(o/i) proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity. OBJECTIVES: In the present studies, subactive doses of mGlu(4) and M(4) activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu(4) and M(4) receptors in animal models of schizophrenia. METHODS: The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects. RESULTS: The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D(2) receptor levels in the striatum, as measured with [(18)F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test. CONCLUSIONS: Based on our results, the simultaneous activation of M(4) and mGlu(4) receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00213-018-4980-y) contains supplementary material, which is available to authorized users.