IFEC, CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende s/n, Ciudad Universitaria, 5000 Córdoba, Argentina.
Synapse. 2011 Feb;65(2):168-80. doi: 10.1002/syn.20831.
The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D₁-like and D₂-like receptors (including D1R or D(1,5)R and D2R or D(2,3,4)R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine-sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage-sensitive Na(+) currents and high voltage-activated Ca(2+) currents, along with increased voltage-gated K(+) currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R-mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine-induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine-induced dysregulation of Ca(2+) homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca(2+) influx preferentially via the L-type Ca(2+) channels and evoked intracellular Ca(2+) release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug-free rats. However, repeated cocaine exposure abolished the D₂R effects on modulating Ca(2+) homeostasis with enhanced PKA activity and led to a decrease in whole-cell Ca(2+) influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal.
伏隔核（NAc）是大脑前脑的边缘结构，在认知功能和成瘾中起着关键作用。多巴胺调节 NAc 中的中脑边缘神经元（MSNs）的活动。多巴胺 D₁样和 D₂样受体（分别包括 D1R 或 D(1,5)R 和 D2R 或 D(2,3,4)R）都被认为在可卡因成瘾中起关键作用。我们之前的研究表明，反复可卡因暴露（改变多巴胺传递）会降低可卡因敏化、戒断大鼠 NAc MSNs 的兴奋性。这种减少的特征是电压敏感的 Na(+)电流和高电压激活的 Ca(2+)电流减少，同时电压门控 K(+)电流增加。这些变化与 D1R/cAMP/PKA/蛋白磷酸酶 1 途径活性增强和钙调神经磷酸酶功能减弱有关。尽管反复可卡因暴露增强了 D1R 介导的信号转导，但尚不清楚 D2R 是否以及如何参与可卡因引起的 NAc 功能障碍。在这里，我们进行了一项联合电生理、生化和神经影像学研究，揭示了 D2R 参与可卡因诱导的 NAc 钙稳态失调。我们的新发现表明，D2R 刺激通过 L 型 Ca(2+)通道优先减少 Ca(2+)内流，并通过抑制 cAMP/PKA 级联反应诱发细胞内 Ca(2+)释放，从而减少在无药物大鼠的 NAc MSNs 中 Ca(2+)内流。然而，反复可卡因暴露消除了 D₂R 对调节 Ca(2+)稳态的作用，增强了 PKA 活性，并导致全细胞 Ca(2+)内流减少。这些适应在可卡因戒断期间持续 21 天，可能有助于可卡因戒断的机制。
