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The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder

Molecular Psychiatry volume 27, pages 4662–4672 (2022)Cite this article

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Abstract

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD.

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Fig. 1: Cardinal features of ADHD.
Fig. 2: Gpr88 mutant mice show ADHD-like behavior in the 5-CSRTT and higher inattention in the ASST.
Fig. 3: Gpr88 mutant mice show higher motor impulsivity in the Go/No-Go task.
Fig. 4: A2A-GPR88 and D1-GPR88 show higher waiting and stopping impulsivity, respectively, in the Go/No-Go task.

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Acknowledgements

This work was supported by the National Institute of Health (National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658), the Canada Fund for Innovation and the Canada Research Chair to BLK. The work was also supported in part by grants from the Fonds de la recherche en santé du Québec and the Canadian Institutes of Health Research to RJ and NG. SMS is a recipient of the Young Investigator Award from the Brain and Behavior Foundation (NARSAD) and Dr. Mortimer D. Sackler Developmental Psychology Investigator Awards. We thank the staff at the animal facility of the Neurophenotyping Center of the Douglas Mental Health University Institute (Montréal, Canada). We also thank present and past members of the ADHD group for technical and clinical assistance.

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Author notes

  1. Sami Ben Hamida

    Present address: INSERM UMR 1247-Research Group on Alcohol & Pharmacodependences (GRAP), Université de Picardie Jules Verne, Amiens, France

  2. Sarojini M. Sengupta

    Present address: AIMH (Artificial Intelligence for Mental Health) Inc., Montreal, QC, Canada

  3. Emmanuel Darcq & Brigitte L. Kieffer

    Present address: INSERM U1114, Département de Psychiatrie, Université de Strasbourg, Strasbourg, France

Authors and Affiliations

  1. Douglas Mental Health University Institute, Montreal, QC, Canada

    Sami Ben Hamida, Sarojini M. Sengupta, Ellie Clarke, Michael McNicholas, Eleonora Moroncini, Emmanuel Darcq, Marie-Ève Fortier, Natalie Grizenko, Ridha Joober & Brigitte L. Kieffer

  2. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Sami Ben Hamida, Sarojini M. Sengupta, Ellie Clarke, Michael McNicholas, Eleonora Moroncini, Emmanuel Darcq, Natalie Grizenko, Ridha Joober & Brigitte L. Kieffer

  3. Department of Educational and Counselling Psychology, McGill University Montreal, Montreal, QC, Canada

    Marina Ter-Stepanian

  4. Department de Psychoéducation, Université de Sherbrooke, Sherbrooke, QC, Canada

    Marina Ter-Stepanian

  5. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Ridha Joober

  6. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Ridha Joober

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Contributions

SBH and BLK designed and led the project, analyzed and interpreted the data and wrote the manuscript. SBH, EC, MM, EM performed mouse behavioral experiments. ED contributed to the project design and edited the manuscript. SMS, MTS, NG, and RJ conceived and designed the genetic/clinical study. SMS, MEF, MTS, NG and RJ performed and analyzed the genetic data. SMS and MTS interpreted the genetic/clinical data and edited the manuscript. All authors gave final approval of the version submitted.

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Correspondence to Brigitte L. Kieffer.

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Competing interests

SBH, SMS, EC, MM, EM, MM, ED, MT-S, M-EF and BLK report no biomedical financial interests or potential competing interests. NG reports receiving research funding from CIHR and is a member of the advisory board for Purdue and Shire. RJ reports having received research funding from CIHR. He is on the advisory boards and speakers’ bureaus of Pfizer, Janssen Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin. He has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer and from Perdue for CME presentations and royalties for Henry Stewart talks.

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Ben Hamida, S., Sengupta, S.M., Clarke, E. et al. The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder. Mol Psychiatry 27, 4662–4672 (2022). https://doi.org/10.1038/s41380-022-01738-w

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