The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson’s disease. However, the development of improved therapeutic strategies has been hampered by our incomplete understanding of this receptor’s downstream signaling processes in vivo and how these relate to the desired and undesired effects of drugs. D2R is a G protein-coupled receptor (GPCR) that activates G protein-dependent as well as non-canonical arrestin-dependent signaling pathways. Whether these effector pathways act alone or in concert to facilitate specific D2R-dependent behaviors is unclear. Here, we report on the development of a D2R mutant that recruits arrestin but is devoid of G protein activity. When expressed virally in “indirect pathway” medium spiny neurons (iMSNs) in the ventral striatum of D2R knockout mice, this mutant restored basal locomotor activity and cocaine-induced locomotor activity in a manner indistinguishable from wild-type D2R, indicating that arrestin recruitment can drive locomotion in the absence of D2R-mediated G protein signaling. In contrast, incentive motivation was enhanced only by wild-type D2R, signifying a dissociation in the mechanisms that underlie distinct D2R-dependent behaviors, and opening the door to more targeted therapeutics.
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We thank Eric Teboul and Jeremy Sherman for technical assistance, and the Rodent Neurobehavioral Analysis Core at the New York Psychiatric Institute.
PD, EFG, DCB, ELS, YZ, and JRL performed the experiments. LMB, KAN, CK, and JAJ supervised the project. PD, EFG, CK, and JAJ wrote the manuscript, with input from JRL, LMB, and KAN. This work was supported by NIH grants DA044696 to PD, MH093672 to CK, DA009158 to LMB, MH54137 and DA022413 to JAJ, MH107648 to EFG, by Merit Review Award BX003279 to KAN from the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research, and Development, by the Lieber Center for Schizophrenia Research, and by the Hope for Depression Research Foundation.
Conflict of interest
The authors declare that they have no conflict of interest.
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Donthamsetti, P., Gallo, E.F., Buck, D.C. et al. Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Mol Psychiatry 25, 2086–2100 (2020). https://doi.org/10.1038/s41380-018-0212-4
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