Serum- and glucocorticoid-inducible kinase 1 activity in ventral tegmental area dopamine neurons regulates cocaine conditioned place preference but not cocaine self-administration
Serum- and glucocorticoid-inducible kinase 1 activity in ventral tegmental area dopamine neurons regulates cocaine conditioned place preference but not cocaine self-administration
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DOI：
10.1038/s41386-021-01032-3
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发表时间：
2021-05-18
影响因子：
7.6
通讯作者：
Mazei-Robison, Michelle S.
中科院分区：
文献类型：
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作者：
Doyle, Marie A.;Bali, Vedrana;Mazei-Robison, Michelle S.
滥用药物调节中脑边缘多巴胺（DA）系统的活性，药物引起的腹侧被盖区（VTA）细胞活性和基因调节的变化与成瘾相关的行为输出有关。我们实验室之前的工作确定，重复给予可卡因可增加 VTA 血清和糖皮质激素诱导激酶 1 (SGK1) 的转录和催化活性；然而，尚不清楚这些生化变化是否会导致可卡因引发的行为。利用转基因和病毒介导的操作，我们研究了 VTA SGK1 催化活性在调节可卡因条件性位置偏好和自我给药中的作用。我们发现，VTA 内输注催化失活的 SGK1 突变体 (K127Q) 可显着降低可卡因条件性位置偏好 (CPP)。此外，我们发现 VTA DA 神经元中的 K127Q 表达显着降低可卡因 CPP，而 VTA GABA 神经元中的相同操作则没有效果。然而，减弱的 VTA DA SGK1 催化活性并不会改变可卡因的自我给药。总而言之，这些研究确定了对 SGK1 介导的可卡因 CPP 作用至关重要的特定 VTA 细胞，但没有确定其自我给药作用。
Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.