Abstract
Orphan G protein Coupled Receptors (GPCRs) present attractive targets both for understanding neuropsychiatric diseases and for development of novel therapeutics. GPR139 is an orphan GPCR expressed in select brain circuits involved in controlling movement, motivation and reward. It has been linked to the opioid and dopamine neuromodulatory systems; however, its role in animal behavior and neuropsychiatric processes is poorly understood. Here we present a comprehensive behavioral characterization of a mouse model with a GPR139 null mutation. We show that loss of GPR139 in mice results in delayed onset hyperactivity and prominent neuropsychiatric manifestations including elevated stereotypy, increased anxiety-related traits, delayed acquisition of operant responsiveness, disruption of cued fear conditioning and social interaction deficits. Furthermore, mice lacking GPR139 exhibited complete loss of pre-pulse inhibition and developed spontaneous ‘hallucinogenic’ head-twitches, altogether suggesting schizophrenia-like symptomatology. Remarkably, a number of these behavioral deficits could be rescued by the administration of μ-opioid and D2 dopamine receptor (D2R) antagonists: naltrexone and haloperidol, respectively, suggesting that loss of neuropsychiatric manifestations in mice lacking GPR139 are driven by opioidergic and dopaminergic hyper-functionality. The inhibitory influence of GPR139 on D2R signaling was confirmed in cell-based functional assays. These observations define the role of GPR139 in controlling behavior and implicate in vivo actions of this receptor in the neuropsychiatric process with schizophrenia-like pathology.
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Acknowledgements
The authors thank Natalia Martemyanova for technical help with mouse husbandry and members of Martemyanov laboratory for helpful discussions. We also wish to thank Drs. Henry Dunn and Subhi Marwari for critical comments on the manuscript.
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MD carried out all of the behavioral experiments, analyzed the data and participated in writing the manuscript. HMS performed signaling assays, analyzed the data and edited the manuscript. YC performed water maze experiments, analyzed the data, and edited the manuscript. KAM conceived the study, analyzed the data and wrote the manuscript.
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Dao, M., Stoveken, H.M., Cao, Y. et al. The role of orphan receptor GPR139 in neuropsychiatric behavior. Neuropsychopharmacol. 47, 902–913 (2022). https://doi.org/10.1038/s41386-021-00962-2
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DOI: https://doi.org/10.1038/s41386-021-00962-2
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