The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies

Wierońska, Joanna M.; Sławińska, Anna; Łasoń, Magdalena; Gruca, Piotr; Papp, Mariusz; Zorn, Stevin H.; Doller, Darı́o; Kłeczek, Natalia; Noworyta-Sokołowska, Karolina; Gołembiowska, Krystyna; Pilc, Andrzej

doi:10.1007/s00213-014-3657-4

Cited by 27 publications

(30 citation statements)

References 53 publications

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“…The present study expands on our recent reports showing that the novel compounds stimulating mGlu 4 receptor, both orthosteric agonists and PAMs, exhibit antipsychotic-like activity in animal models, widely used to study antipsychotic-like activity of drugs [ 15 - 17 , 33 ]. Herein, we describe the activity of the agonist of group III mGlu receptors, LSP4-2022 [ 34 ].…”

Section: Discussionsupporting

confidence: 64%

“…On the other hand, the use of lower doses of the compounds may reduce the risk of adverse effects that are often associated with higher doses. In a series of our previous experiments, we suggested that the interaction between mGlu 4 and 5-HT 1A receptors may be a good antipsychotic target [ 16 , 33 ]. In the present study, we showed that the therapy based on the interaction between mGlu 4 and GABA B receptors may prove beneficial for patients with a predominance of positive symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of GABA_BReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu₄Receptor, LSP4-2022

Woźniak¹,

Acher²,

Marciniak³

et al. 2016

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Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Involvement of GABA_BReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu₄Receptor, LSP4-2022

Woźniak¹,

Acher²,

Marciniak³

et al. 2016

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“…The basic assumption of the study was to establish if the administration of subeffective doses of the ligands of those receptors would exert antipsychotic-like activity without inducing adverse effects typical for standard dopamine-based antipsychotics. Such simultaneous action of the combined treatment was reported previously for subeffective doses of mGlu 4 -5-HT 1A receptor ligands (Wierońska et al 2013 , 2015 ). In addition, studies were undertaken with the combined administration of mGlu 4 and GABA B activators, but the efficacy of subeffective doses of the combination of these ligands was not evident in the models of negative and cognitive symptoms of schizophrenia, although the ligands exerted antipsychotic efficacy when active doses of each compound were administered alone (Wierońska et al 2015 ; Woźniak et al 2016 ).…”

Section: Introductionsupporting

confidence: 76%

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

et al. 2018

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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.

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“…The spatial delayed alternation test was performed using a wooden T-maze, according to Sławińska et al, 2013 and Wierońska et al, 2015b .…”

Section: Methodsmentioning

confidence: 99%

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs

Cieślik

Woźniak

Kaczorowska

et al. 2018

Front. Mol. Neurosci.

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The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25–0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

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The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies

Cited by 27 publications

References 53 publications

Involvement of GABA_BReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu₄Receptor, LSP4-2022

Involvement of GABA_BReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu₄Receptor, LSP4-2022

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

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs

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The antipsychotic-like effects in rodents of the positive allosteric modulator Lu AF21934 involve 5-HT1A receptor signaling: mechanistic studies

Cited by 27 publications

References 53 publications

Involvement of GABABReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4Receptor, LSP4-2022

Involvement of GABABReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4Receptor, LSP4-2022

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

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs

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Involvement of GABA_BReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu₄Receptor, LSP4-2022

Involvement of GABA_BReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu₄Receptor, LSP4-2022