Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons
Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons
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DOI：
10.1111/j.1471-4159.2004.02574.x
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发表时间：
2004-09-01
影响因子：
4.7
通讯作者：
Nishi, A
中科院分区：
文献类型：
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作者：
Hamada, M;Higashi, H;Nishi, A
尼古丁作用于突触前多巴胺能末端表达的烟碱乙酰胆碱受体（nAChR），已被证明可以刺激新纹状体释放多巴胺。然而，突触前 nAChR 激活在突触后新纹状体神经元中的分子后果尚不清楚。在这里，我们通过测量小鼠新纹状体切片中 Thr34（PKA 位点）的磷酸化 DARPP-32（多巴胺和 cAMP 调节的 M-r 32 kDa 磷酸蛋白），研究了 nAChR 激活对中型多棘神经元多巴胺能信号传导的影响。尼古丁产生剂量依赖性反应，低浓度（1μM）导致DARPP-32 Thr34磷酸化持续减少，高浓度（100μM）导致DARPP-32 Thr34磷酸化短暂增加。根据尼古丁的浓度，多巴胺 D2 或 D1 受体信号传导主要被激活。低浓度（1 μM）的尼古丁可能通过激活多巴胺能末端的 alpha4beta2* nAChR 来激活纹状体苍白球/间接通路神经元中的多巴胺 D2 受体信号传导。高浓度（100 μM）的尼古丁激活纹状体黑质/直接通路神经元中的多巴胺 D1 受体信号传导，可能是通过激活（i）多巴胺能末端的 α4β2* nAChR 和（ii）谷氨酸能末端的 α7 nAChR，后者通过刺激谷氨酸的释放，激活多巴胺能末端的 NMDA/AMPA 受体。低尼古丁浓度和高尼古丁浓度对纹状体神经元 D2 和 D1 依赖性信号通路的不同影响可能导致这种滥用药物的剂量依赖性作用。
Nicotine, acting on nicotinic acetylcholine receptors (nAChRs) expressed at pre-synaptic dopaminergic terminals, has been shown to stimulate the release of dopamine in the neostriatum. However, the molecular consequences of pre-synaptic nAChR activation in post-synaptic neostriatal neurons are not clearly understood. Here, we investigated the effect of nAChR activation on dopaminergic signaling in medium spiny neurons by measuring phosphorylated DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M-r 32 kDa) at Thr34 (the PKA-site) in mouse neostriatal slices. Nicotine produced dose-dependent responses, with a low concentration (1 muM) causing a sustained decrease in DARPP-32 Thr34 phosphorylation and a high concentration (100 muM) causing a transient increase in DARPP-32 Thr34 phosphorylation. Depending on the concentration of nicotine, either dopamine D2 or D1 receptor signaling was predominantly activated. Nicotine at a low concentration (1 muM) activated dopamine D2 receptor signaling in striatopallidal/indirect pathway neurons, likely by activating alpha4beta2* nAChRs at dopaminergic terminals. Nicotine at a high concentration (100 muM) activated dopamine D1 receptor signaling in striatonigral/direct pathway neurons, likely by activating (i) alpha4beta2* nAChRs at dopaminergic terminals and (ii) alpha7 nAChRs at glutamatergic terminals, which, by stimulating the release of glutamate, activated NMDA/AMPA receptors at dopaminergic terminals. The differential effects of low and high nicotine concentrations on D2- and D1-dependent signaling pathways in striatal neurons may contribute to dose-dependent actions of this drug of abuse.