Mutual activation of glutamatergic mGlu4 and muscarinic M4 receptors reverses schizophrenia-related changes in rodents

Abstract

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.

Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice

“…Schedules of administration are presented graphically in Figure 1. The sub-effective doses of VU152100 for each test (0.25 mg/kg for novel object recognition and 0.5 mg/kg for social interaction) were chosen based on our previous research (see [18]). Different vehicles were used throughout the study: (1) 0.9% NaCl, (2) 10% Tween 80 or (3) 10% Tween 80 containing 2% DMSO.…”

“…Acute administration of MK-801 is a well-established model of schizophrenia, with high predictive validity for investigating the antipsychotic-like activity of compounds. This model is widely used in a variety of studies, including those performed in our laboratory (for example, [7,18]). Using this model, we showed antipsychotic-like activity of VU152100 in social interaction and in novel object recognition tests [18,30].…”

“…Both receptors are expressed in the cerebral cortex, striatum and hippocampus, which are brain regions of particular importance in schizophrenia [15,16], and disturbances in the expression of M 4 receptor in schizophrenia patients have been confirmed by some post mortem studies [17]. A growing body of preclinical studies shows that mGlu 2 and M 4 receptor stimulation reverses deficits observed in animal models of schizophrenia [18,19,20,21,22,23,24,25]. mGlu 2 ligands were also studied in clinical trials with mixed results (initial positive data on antipsychotic activity of mGlu 2 ligands in schizophrenic patients were contradicted by subsequent Phase III studies) [26,27], and there is no available clinical data concerning selective M 4 ligands.…”

“…In our previous research it was shown that positive allosteric modulator (PAM) of M 4 receptor, VU152100, alone and in combined administration with the orthosteric agonist of mGlu 4 receptor, LSP4-2022, was effective in animal models of schizophrenia, such as MK-801- or amphetamine-induced hyperactivity, DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches, modified forced swim test, MK-801-induced disruptions in social interactions and novel object recognition test [18].…”

The Role of Metabotropic Glutamate Receptors in Social Behavior in Rodents

“…Similarly, other studies have shown that activation of mGluR4 with the mGluR4 agonist (2S)-2-amino-4-({[4-(carboxymethoxy)phenyl](hydroxy)methyl}(hydroxy)phosphoryl)butanoic acid (LSP4-2022) and the PAMs of mGluR4 (1S,2R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) and (E)-4-(2-Phenylethenyl)-2-pyrimidinamine (Lu AF32615) reduced the social interaction deficits induced by the NMDA receptor antagonist MK-801 in rats [102,103,104]. Interestingly, the social interaction deficits induced by MK-801 were not only prevented by pretreatment with LSP4-2022 in mice, but also by a concomitant administration of sub-effective doses of LSP4-2022 and 3-Amino- N -(4-methoxybenzyl)-4,6-dimethylthieno[2,3- b ]pyridine carboxamide (VU152100), a PAM of muscarinic M4 receptor, suggesting that simultaneous activation of mGluR4 and M4 receptors might be beneficial in preventing social interaction deficits elicited by an impaired NMDA receptor function [105].…”