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

Neuropharmacology. 2022 May 10:109078. doi: 10.1016/j.neuropharm.2022.109078. Online ahead of print.ABSTRACTApathy, 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 Ca2+ 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...

Source: Neuropharmacology - May 13, 2022 Category: Drugs & Pharmacology Authors: Alexandra M ünster Susanne Sommer Diana K úkeľová Hannes Sigrist Eliza Koros Serena Deiana Klaus Klinder Tamara Baader-Pagler Svenja Mayer-Wrangowski Boris Ferger Tom Bretschneider Christopher R Pryce Wolfgang Hauber Moritz von Heimendahl Source Type: research