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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >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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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.

机译：在甲基苯丙胺致敏过程中，多巴胺D3受体突变体中边缘多巴胺D1受体介导的信号转导和Akt / GSK3途径的双重改变。

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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.
机译：中枢多巴胺系统在运动活动和药物引起的行为敏化中起重要作用。我们的目标是确定多巴胺D（3）受体在对甲基苯丙胺的行为敏化发展中的重要性，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对急性甲基苯丙胺的行为反应，并引起了对慢性甲基苯丙胺的行为敏化的更快速率。此外，在致敏的野生型小鼠中，边缘前脑的D（3）受体蛋白和mRNA水平均降低。进一步的分析表明，与致敏的野生型小鼠相比，致敏的D（3）突变体增加了D（1）依赖的行为敏化和边缘性​​D（1）受体的数量。符合此发现，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DARPP-32 / Thr34的水平高于野生型小鼠，且在慢性甲基苯丙胺后这种差异更为明显治疗。我们还观察到磷酸化细胞外信号调节激酶2的增加，但与野生型小鼠相比，D（3）突变体的边缘前脑中的磷酸化Akt / Ser473和磷酸糖原合酶激酶3（GSK3）-alpha / beta降低甲基苯丙胺治疗。收敛的结果暗示D（3）受体作为甲基苯丙胺致敏发展的负调节剂。 D（1）受体介导的信号的补偿性上调，除了改变的Akt / GSK3途径外，还可能有助于行为敏化的加速发展。

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