Dual alteration of limbic dopamine D1 receptor-mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization
Dual alteration of limbic dopamine D1 receptor-mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization
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DOI：
10.1111/j.1471-4159.2006.04203.x
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发表时间：
2007-01-01
影响因子：
4.7
通讯作者：
Chen, Jin-Chung
中科院分区：
文献类型：
--
作者：
Chen, Pei-Chun;Lao, Chu-Lan;Chen, Jin-Chung
中枢多巴胺系统在运动活动和药物诱导的行为敏化中起重要作用。我们的目标是确定多巴胺D-3受体在甲基苯丙胺行为致敏发展中的意义，用D-3受体突变小鼠进行评估。D-3受体的缺乏显着增加了急性甲基苯丙胺的行为反应，并诱发了更快的速度的行为敏化慢性甲基苯丙胺。此外，在致敏野生型小鼠中，边缘前脑中的D-3受体蛋白和mRNA水平均降低。进一步的分析表明，与致敏野生型小鼠相比，致敏D-3突变体的D-1依赖性行为致敏和边缘D-1受体数量增加。与这一发现相一致，我们观察到D-3突变体的边缘前脑中D-1受体诱发的cAMP积累和基础磷酸化DARPP-32/Thr 34水平高于野生型小鼠，并且在慢性甲基苯丙胺治疗后差异更加明显。我们还观察到增加磷酸细胞外信号调节激酶2，但减少磷酸Akt/Ser 473和磷酸糖原合成酶激酶3（GSK 3）-α/β在边缘前脑的D-3突变体与野生型小鼠相比，甲基苯丙胺治疗后。收敛的结果牵连D-3受体作为负调节甲基苯丙胺致敏的发展。D-1受体介导的信号的补偿性上调，以及Akt/GSK 3通路的改变，可能有助于行为敏感化的加速发展。
The central dopamine system plays significant roles in motor activity and drug-induced behavioural sensitization. Our goal was to determine the significance of dopamine D-3 receptors in the development of behavioural sensitization to methamphetamine, assessed with D-3 receptor mutant mice. The absence of D-3 receptors significantly increased the behavioural responses to acute methamphetamine and evoked a faster rate of behavioural sensitization to chronic methamphetamine. In addition, both D-3 receptor protein and mRNA levels in the limbic forebrain decreased in sensitized wild-type mice. Further analyses indicated that D-1-dependent behavioural sensitization and the number of limbic D-1 receptors increased in sensitized D-3 mutants as compared with sensitized wild-type mice. Consistent with this finding, we observed higher levels of D-1 receptor-evoked cAMP accumulation and basal phosphoDARPP-32/Thr34 in the limbic forebrain of D-3 mutants than wild-type mice and the difference was more pronounced after chronic methamphetamine treatment. We also observed an increase in phospho-extracellular signal-regulated kinase 2 but a decrease in phosphoAkt/Ser473 and phosphoglycogen synthase kinase 3 (GSK3)-alpha/beta in the limbic forebrain of D-3 mutants compared with wild-type mice after methamphetamine treatment. The convergent results implicate D-3 receptors as a negative regulator of the development of methamphetamine sensitization. A compensatory up-regulation of D-1 receptor-mediated signals, in addition to an altered Akt/GSK3 pathway, could contribute to the accelerated development of behavioural sensitization.