Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions.

Autor: Münster A; Systems Neurobiology Research Unit, University of Stuttgart, Stuttgart, Germany., Sommer S; Systems Neurobiology Research Unit, University of Stuttgart, Stuttgart, Germany., Kúkeľová D; Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) and University of Zurich (UZH), Zurich, Switzerland., Sigrist H; Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) and University of Zurich (UZH), Zurich, Switzerland., Koros E; CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Deiana S; CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Klinder K; Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Baader-Pagler T; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Mayer-Wrangowski S; Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Ferger B; CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany; Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Bretschneider T; Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany., Pryce CR; Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich (PUK) and University of Zurich (UZH), Zurich, Switzerland; Neuroscience Center Zurich, Zurich, Switzerland., Hauber W; Systems Neurobiology Research Unit, University of Stuttgart, Stuttgart, Germany., von Heimendahl M; CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. Electronic address: moritz.von_heimendahl@boehringer-ingelheim.com.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2022 Aug 01; Vol. 213, pp. 109078. Date of Electronic Publication: 2022 May 10.
DOI: 10.1016/j.neuropharm.2022.109078
Abstrakt: Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca 2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy.
(Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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