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      Involvement of GABA B Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu 4 Receptor, LSP4-2022

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          Abstract

          Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu 4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABA B 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 mGlu 4 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. GABA B 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 GABA B receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu 4 and GABA B receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu 4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu 4 and GABA B receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.

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          Most cited references 47

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          Pharmacology and functions of metabotropic glutamate receptors.

           J P Pin,  P. Conn (1996)
          In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
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            Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.

            Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.
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              • Article: not found

              The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents.

              Rats and mice are attracted by novel objects. They readily approach novel objects and explore them with their vibrissae, nose and forepaws. It is assumed that such a single explorative episode leaves a lasting and complex memory trace, which includes information about the features of the object explored, as well as where and even when the object was encountered. Indeed, it has been shown that rodents are able to discriminate a novel from a familiar object (one-trial object recognition), can detect a mismatch between the past and present location of a familiar object (one-trial object-place recognition), and can discriminate different objects in terms of their relative recency (temporal order memory), i.e., which one of two objects has been encountered earlier. Since the novelty-preference paradigm is very versatile and has some advantages compared to several other memory tasks, such as the water maze, it has become a powerful tool in current neurophamacological, neuroanatomical and neurogenetical memory research using both rats and mice. This review is intended to provide a comprehensive summary on key findings delineating the brain structures, neurotransmitters, molecular mechanisms and genes involved in encoding, consolidation, storage and retrieval of different forms of one-trial object memory in rats and mice.
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                Author and article information

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                CN
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                July 2016
                July 2016
                : 14
                : 5
                : 413-426
                Affiliations
                [1 ]Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków,Poland;
                [2 ]UMR8601-CNRS, Université Paris Descartes, 45 rue des Saints-Pères, France;
                [3 ]Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, 31-531 Kraków,Poland
                Author notes
                [* ]Address correspondence to this author at the Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland; Tel: +48 12 66 23 288; Fax: +48 12 637 45 00; E-mail: wierons@ 123456if-pan.krakow.pl
                Article
                CN-14-413
                10.2174/1570159X13666150516000630
                4983756
                26769224
                © 2016 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                Categories
                Article

                Pharmacology & Pharmaceutical medicine

                gabab, lsp4-2022, mglu4, schizophrenia

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