• Genghong Tu, Li Ying, Liuzhen Ye, Jinlan Zhao, Nuyun Liu, Juan Li, Yutong Liu, Mengjuan Zhu, Yue Wu, Bin Xiao, Huidong Guo, Fukun Guo, Huijun Wang, Lin Zhang, and Lu Zhang.
• Key Laboratory of Functional Proteomics of Guangdong Province, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
• Biol. Psychiatry. 2019 Dec 1; 86 (11): 820-835.

BackgroundMethamphetamine (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.MethodsUsing 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.ResultsD1Rs 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.ConclusionsD1Rs 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.Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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