Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia.

LSP4-2022 is a novel, orthosteric agonist of mGlu receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT receptors in LSP4-2022-induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5-2 mg/kg) were antagonized via the administration of the 5-HT antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT agonist (R)-(S)-8-OH-DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4-2022, having no influence on the efficacy of the active doses. The co-administration of effective doses of both compounds did not intensify each other's action. In the microdialysis in vivo tests, MK-801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4-2022 (2 mg/kg) abolished this MK-801-induced effect on neurotransmitter release. Co-administration with WAY100635 (0.1 mg/kg), a 5-HT antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4-2022-induced effect. Subsequently, the patch-clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 μM). LSP4-2022 (2.5; 5 and 10 μm) reversed DOI-induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4-2022-induced effects on sEPSCs, indicating that the mGlu-5-HT interaction does not occur via single-neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

RationaleMetabotropic glutamate receptors and muscarinic M4 receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to Go/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.ObjectivesIn the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia.MethodsThe 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.ResultsThe 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 D2 receptor levels in the striatum, as measured with [18F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.ConclusionsBased on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.Electronic supplementary materialThe online version of this article (10.1007/s00213-018-4980-y) contains supplementary material, which is available to authorized users.