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How changes in dopamine D2 receptor levels alter striatal circuit function and motivation

Abstract

It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.

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Fig. 1: A simplified circuit diagram and the locations of D2 receptors in the basal ganglia.
Fig. 2: Signaling pathways elicited by D2R activation.
Fig. 3: Schematic diagram of the operant progressive ratio (PR) task.

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Acknowledgements

This manuscript has been based on research funded by NIH MH107648 for E.F.G., NIH MH068073 for P.B, NIH MH054137 and Hope for Depression Research Foundation for J.A.J. and NIH MH093672 for C.K. Figures were created with BioRender.com.

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EHS, EFG and CK wrote the initial version and edited the manuscript. PB and JAJ added to and edited the manuscript.

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Correspondence to Eleanor H. Simpson or Christoph Kellendonk.

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Simpson, E.H., Gallo, E.F., Balsam, P.D. et al. How changes in dopamine D2 receptor levels alter striatal circuit function and motivation. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01253-4

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