Role of Aberrant Striatal Dopamine D1 Receptor/cAMP/Protein Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect of Amphetamine
Role of Aberrant Striatal Dopamine D1 Receptor/cAMP/Protein Kinase A/DARPP32 Signaling in the Paradoxical Calming Effect of Amphetamine
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DOI：
10.1523/jneurosci.1682-10.2010
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发表时间：
2010-08-18
影响因子：
5.3
通讯作者：
Usiello, Alessandro
中科院分区：
文献类型：
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作者：
Napolitano, Francesco;Bonito-Oliva, Alessandra;Usiello, Alessandro
注意力缺陷/多动障碍 (ADHD) 的特点是注意力不集中、冲动和运动过度活跃。多项研究支持多巴胺转运蛋白（DAT）基因在这种精神疾病中发挥着至关重要的作用。一直以来，ADHD 治疗中最常用的处方药物是兴奋剂药物，已知其优先作用于 DAT。最近，已经产生了一种携带可卡因不敏感 DAT 的敲入小鼠 [DAT 可卡因不敏感 (DAT-CI)]，该小鼠具有功能，但多巴胺摄取功能降低。 DAT-CI 突变体表现出增强的纹状体细胞外多巴胺水平和基础运动亢进。在此，我们发现 DAT-CI 动物表现出更高的纹状体多巴胺周转，改变了多巴胺和 cAMP 调节的磷蛋白 32kDa (DARPP32) Thr75 残基的基础磷酸化状态，但保留了 D-2 受体 (D2R) 功能。然而，尽管我们证明纹状体 D-1 受体 (D1R) 在基础条件下具有生理反应，但其刺激诱导的激活却惊人地导致了矛盾的电生理、行为和生化反应。事实上，在 DAT-CI 动物中，(1) 纹状体 LTP 完全被破坏，(2) R-(+)-6-氯-7,8-二羟基-1-苯基-2,3,4,5-四氢-1H-3-苯并氢溴酸盐 (SKF 81297) 治疗诱导了矛盾的运动镇静作用，(3) SKF 81297 给药未能增加 cAMP/蛋白激酶 A (PKA)/DARPP32 信号传导。这种生化改变选择性地影响多巴胺 D(1)Rs，因为氟哌啶醇通过阻断 D2R 的强直性抑制，揭示了突变体中纹状体腺苷 A(2A) 受体介导的 cAMP/PKA/DARPP32 级联的正常激活。最重要的是，我们的研究强调，安非他明、诺米芬辛和安非他酮通过增加纹状体多巴胺能传递，能够恢复 DAT-CI 动物的运动过度活跃。总体而言，我们的结果表明，这些药物在 DAT-CI 突变体中诱导的矛盾运动镇静作用取决于 D1R/cAMP/PKA/DARPP32 信号传导响应纹状体细胞外多巴胺水平增加的选择性异常阶段性激活。
Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32kDa (DARPP32) at Thr75 residue, but preserved D-2 receptor (D2R) function. However, although we demonstrated that striatal D-1 receptor (D1R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D2R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D1R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.