BACKGROUND Methamphetamine (METH) is a highly addictive psychostimulant that strongly activates dopamine receptor signaling in the nucleus accumbens (NAc). However, how dopamine D1 and D2 receptors (D1Rs and D2Rs, respectively) as well as downstream signaling pathways, such as those involving Rac1 and Cdc42, modulate METH-induced behavioral and structural plasticity is largely unknown. METHODS Using NAc conditional D1R and D2R deletion mice, Rac1 and Cdc42 mutant viruses, and a series of behavioral and morphological methods, we assessed the effects of D1Rs and D2Rs on Rac1 and Cdc42 in modulating METH-induced behavioral and structural plasticity in the NAc. RESULTS D1Rs and D2Rs in the NAc consistently regulated METH-induced conditioned place preference, locomotor activation, and dendritic and spine remodeling of medium spiny neurons but differentially regulated METH withdrawal-induced spatial learning and memory impairment and anxiety. Interestingly, Rac1 and Cdc42 signaling were oppositely modulated by METH, and suppression of Rac1 signaling and activation of Cdc42 signaling were crucial to METH-induced conditioned place preference and structural plasticity but not to locomotor activation. D1Rs activated Rac1 and Cdc42 signaling, while D2Rs inhibited Rac1 signaling but activated Cdc42 signaling to mediate METH-induced conditioned place preference and structural plasticity but not locomotor activation. In addition, NAc D1R deletion aggravated METH withdrawal-induced spatial learning and memory impairment by suppressing Rac1 signaling but not Cdc42 signaling, while NAc D2R deletion aggravated METH withdrawal-induced anxiety without affecting Rac1 or Cdc42 signaling. CONCLUSIONS D1Rs and D2Rs differentially regulate Rac1 and Cdc42 signaling to modulate METH-induced behavioral plasticity and the structural remodeling of medium spiny neurons in the NAc.

中文翻译：

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多巴胺 D1 和 D2 受体差异调节伏隔核中的 Rac1 和 Cdc42 信号，以调节重复甲基苯丙胺治疗后的行为和结构可塑性

背景甲基苯丙胺（METH）是一种高度成瘾的精神兴奋剂，它强烈激活伏隔核（NAc）中的多巴胺受体信号。然而，多巴胺 D1 和 D2 受体（分别为 D1R 和 D2R）以及下游信号通路（例如涉及 Rac1 和 Cdc42 的通路）如何调节 METH 诱导的行为和结构可塑性在很大程度上是未知的。方法使用 NAc 条件性 D1R 和 D2R 缺失小鼠、Rac1 和 Cdc42 突变病毒，以及一系列行为和形态学方法，我们评估了 D1Rs 和 D2Rs 对 Rac1 和 Cdc42 在调节 NAc 中 METH 诱导的行为和结构可塑性方面的影响。结果 NAc 中的 D1Rs 和 D2Rs 始终如一地调节 METH 诱导的条件性位置偏好、运动激活、中等多刺神经元的树突和脊柱重塑，但不同地调节 METH 戒断诱导的空间学习和记忆障碍和焦虑。有趣的是，Rac1 和 Cdc42 信号受到 METH 的相反调节，抑制 Rac1 信号和激活 Cdc42 信号对 METH 诱导的条件性位置偏好和结构可塑性至关重要，但对运动激活则不然。D1Rs 激活 Rac1 和 Cdc42 信号，而 D2Rs 抑制 Rac1 信号但激活 Cdc42 信号以介导 METH 诱导的条件性位置偏好和结构可塑性，但不能激活运动。此外，NAc D1R 缺失通过抑制 Rac1 信号而不是 Cdc42 信号来加重 METH 戒断诱导的空间学习和记忆障碍，而 NAc D2R 缺失会加重 METH 戒断引起的焦虑，而不影响 Rac1 或 Cdc42 信号。结论 D1Rs 和 D2Rs 差异调节 Rac1 和 Cdc42 信号以调节 METH 诱导的行为可塑性和 NAc 中中等多刺神经元的结构重塑。