Dopamine D₁ and D₂ Receptors Differentially Regulate Rac1 and Cdc42 Signaling in the Nucleus Accumbens to Modulate Behavioral and Structural Plasticity After Repeated Methamphetamine Treatment

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.