Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation

Donthamsetti, Prashant; Gallo, Eduardo F.; Buck, David C.; Stahl, Edward L.; Zhu, Ying; Lane, J. Robert; Bohn, Laura M.; Neve, Kim A.; Kellendonk, Christoph; Javitch, Jonathan A.

Abstract

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.

Citation

Donthamsetti, P., Gallo, E. F., Buck, D. C., Stahl, E. L., Zhu, Y., Lane, J. R., Bohn, L. M., Neve, K. A., Kellendonk, C., & Javitch, J. A. (2018). Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Molecular Psychiatry, 25, 2086–2100. https://doi.org/10.1038/s41380-018-0212-4

• Journal Article Type: Article
• Acceptance Date: Jun 25, 2018
• Online Publication Date: Aug 17, 2018
• Publication Date: 2018-09
• Deposit Date: Apr 22, 2020
• Publicly Available Date: Apr 29, 2020
• Journal: Molecular Psychiatry
• Print ISSN: 1359-4184
• Electronic ISSN: 1476-5578
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Pages: 2086–2100
• DOI: https://doi.org/10.1038/s41380-018-0212-4
• Public URL: https://nottingham-repository.worktribe.com/output/1339495
• Publisher URL: https://www.nature.com/articles/s41380-018-0212-4
• Related Public URLs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378141/