Neuroscience Program, Michigan State University, 766 Service Rd, ISTB 5017, East Lansing, MI, 48824, USA.
Department of Molecular and Systems Biology, Dartmouth University, Hanover, USA.
Sci Rep. 2020 Sep 8;10(1):14751. doi: 10.1038/s41598-020-71681-9.
Drugs of abuse cause significant neuroadaptations within the ventral tegmental area (VTA), with alterations in gene expression tied to changes in reward behavior. Serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription, catalytic activity, and phosphorylation are upregulated in the VTA by chronic cocaine or morphine treatment, positioning SGK1 as a critical mediator of reward behavior. Using transgenic mouse models, we investigated the effect of SGK1 knockout in the VTA and in dopamine (DA) neurons to evaluate the necessity of protein expression for natural and drug reward behaviors. SGK1 knockdown in the VTA did not impact reward behaviors. Given VTA cellular heterogeneity, we also investigated a DA neuron-specific SGK1 knockout (KO). DA SGK1 KO significantly decreased body weight of adult mice as well as increased general locomotor activity; however, reward behaviors were similarly unaltered. Given that SGK1 mutants virally overexpressed in the VTA are capable of altering drug-associated behavior, our current results suggest that changes in SGK1 protein signaling may be distinct from expression. This work yields novel information on the impact of SGK1 deletion, critical for understanding the role of SGK1 signaling in the central nervous system and evaluating SGK1 as a potential therapeutic target for treatment of substance use disorders.
滥用药物会导致腹侧被盖区（VTA）发生显著的神经适应性变化，基因表达的改变与奖励行为的变化有关。慢性可卡因或吗啡处理会使 VTA 中的血清和糖皮质激素诱导激酶 1（SGK1）转录、催化活性和磷酸化上调，使 SGK1 成为奖励行为的关键介质。使用转基因小鼠模型，我们研究了 VTA 和多巴胺（DA）神经元中 SGK1 敲除对自然和药物奖励行为的影响，以评估蛋白质表达对自然和药物奖励行为的必要性。VTA 中的 SGK1 敲低不会影响奖励行为。鉴于 VTA 细胞的异质性，我们还研究了一种 DA 神经元特异性 SGK1 敲除（KO）。DA SGK1 KO 显著降低成年小鼠的体重，同时增加一般运动活性；然而，奖励行为也没有改变。鉴于在 VTA 中过表达的 SGK1 突变体能够改变与药物相关的行为，我们目前的结果表明，SGK1 蛋白信号的变化可能与表达不同。这项工作提供了关于 SGK1 缺失影响的新信息，这对于理解 SGK1 信号在中枢神经系统中的作用以及评估 SGK1 作为治疗物质使用障碍的潜在治疗靶点至关重要。
