Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward
Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward
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DOI：
10.1038/sj.npp.1301321
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发表时间：
2007-09-01
影响因子：
7.6
通讯作者：
Fisone, Gilberto
中科院分区：
文献类型：
--
作者：
Borgkvist, Anders;Usiello, Alessandro;Fisone, Gilberto
纹状体多巴胺感受神经元中cAMP/PKA通路的激活已被提出介导各种滥用药物的作用。在这里，我们表明，在小鼠延髓核和背侧纹状体，吗啡的急性给药导致在Thr 34的多巴胺和cAMP调节的磷蛋白32 kDa（DARPP-32）的磷酸化状态的增加，而不影响Thr 75的磷酸化。阻断多巴胺D1受体可以阻止吗啡刺激Thr 34磷酸化的能力。DARPP-32敲除小鼠和T34 A DARPP-32突变小鼠对单次注射吗啡的过度运动反应低于野生型对照。相比之下，在T75 A DARPP-32突变小鼠中，吗啡诱导的精神活动与野生型同窝小鼠的精神活动没有区别。尽管DARPP-32基因敲除小鼠和T34 A DARPP-32突变小鼠对吗啡的急性过度运动效应的反应降低，但它们能够发展出与野生型对照相当的对吗啡的行为敏化，并显示出吗啡条件性位置偏爱。这些结果表明，多巴胺D1受体介导的激活的cAMP/DARPP-32级联在纹状体中型多刺神经元参与的精神的行动，但不是在奖励性质，吗啡。
Activation of the cAMP/PKA pathway in the dopaminoceptive neurons of the striatum has been proposed to mediate the actions of various classes of drugs of abuse. Here, we show that, in the mouse nucleus accumbens and dorsal striatum, acute administration of morphine resulted in an increase in the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa ( DARPP-32) at Thr34, without affecting phosphorylation at Thr75. The ability of morphine to stimulate Thr34 phosphorylation was prevented by blockade of dopamine D1 receptors. DARPP-32 knockout mice and T34A DARPP-32 mutant mice displayed a lower hyperlocomotor response to a single injection of morphine than wild-type controls. In contrast, in T75A DARPP-32 mutant mice, morphine-induced psychomotor activation was indistinguishable from that of wild-type littermates. In spite of their reduced response to the acute hyperlocomotor effect of morphine, DARPP-32 knockout mice and T34A DARPP-32 mutant mice were able to develop behavioral sensitization to morphine comparable to that of wild-type controls and to display morphine conditioned place preference. These results demonstrate that dopamine D1 receptor-mediated activation of the cAMP/DARPP-32 cascade in striatal medium spiny neurons is involved in the psychomotor action, but not in the rewarding properties, of morphine.