Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia^1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning^3,4,5. 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 A_2A receptor (A_2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca²⁺/calmodulin-dependent protein kinase II and A_2ARs 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.

多巴胺 D2 受体 (D2Rs) 在纹状体中密集表达，并与精神分裂症等神经精神疾病有关^1,2。多巴胺的高亲和力结合表明 D2R 在惩罚学习^3,4,5期间检测到多巴胺浓度的瞬时降低（多巴胺下降） 。然而，D2R 依赖行为的性质和细胞基础尚不清楚。在这里，我们展示了音调奖励条件反射以依赖于小鼠伏隔核 (NAc) 中的多巴胺 D1 受体 (D1Rs) 的方式诱导显着的刺激泛化，并且辨别学习使用多巴胺浸提来改进条件反射。在 NAc 切片中，D2R 检测到狭窄的多巴胺下降（短至 0.4 s）以去抑制腺苷 A _2A受体（A_2A R) 介导的 D2R 表达的棘状投射神经元 (D2-SPN) 中的树突棘增大。^{NAc 中的 Ca 2+} /钙调蛋白依赖性蛋白激酶 II 和 A _2A Rs 的可塑性相关信号传导是辨别学习所必需的。相比之下，灭绝学习不涉及多巴胺下降或 D2-SPN。用甲基苯丙胺治疗，它会失调多巴胺信号传导，损害辨别学习和脊柱增大，并且这些损伤被 D2R 拮抗剂逆转。我们的数据表明，D2Rs 改进了由 D1Rs 介导的广义奖励学习。