Dopamine D2 receptors in discrimination learning and spine enlargement

Yusuke Iino, Takeshi Sawada, Kenji Yamaguchi, Mio Tajiri, Shin Ishii, Haruo Kasai () and Sho Yagishita ()
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Yusuke Iino: The University of Tokyo
Takeshi Sawada: The University of Tokyo
Kenji Yamaguchi: The University of Tokyo
Mio Tajiri: The University of Tokyo
Shin Ishii: The University of Tokyo
Haruo Kasai: The University of Tokyo
Sho Yagishita: The University of Tokyo

Nature, 2020, vol. 579, issue 7800, 555-560

Abstract: Abstract Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3–5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.

Date: 2020
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DOI: 10.1038/s41586-020-2115-1

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