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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.


Prashant Donthamsetti

Eduardo F. Gallo

David C. Buck

Edward L. Stahl

Ying Zhu

Associate Professor

Laura M. Bohn

Kim A. Neve

Christoph Kellendonk

Jonathan A. Javitch


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.


Donthamsetti, P., Gallo, E. F., Buck, D. C., Stahl, E. L., Zhu, Y., Lane, J. R., …Javitch, J. A. (2018). Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Molecular Psychiatry, 25, 2086–2100.

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
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