Wojcieszak Jakub, Kuczyńska Katarzyna, Leszczyńska Adrianna, Naraziński Eryk, Cichalewska-Studzińska Maria
Department of Pharmacodynamics, Medical University of Lodz, Muszyńskiego 1, Łódź, 90-151, Poland.
Research Laboratory CoreLab of the Medical University of Lodz, Łódź, Poland.
Pharmacol Rep. 2025 Apr;77(2):434-449. doi: 10.1007/s43440-025-00701-0. Epub 2025 Jan 27.
The current study investigated the effects of high-fat diet on acute response to 3,4-methylenedioxypyrovalerone (MDPV) in mice. MDPV is a beta-cathinone derivative endowed with psychostimulant activity. Similarly to recreational substances, consumption of palatable food stimulates the mesolimbic dopaminergic system, resulting in neuroadaptive changes.
Adolescent C57BL/6N mice were fed either control diet (CD), 10% of kcal from fat, or high-fat diet (HFD), 60% of kcal from fat. After eight weeks, one group of HFD-fed mice had their diet changed to CD for an additional two weeks. Fasting glucose levels and glucose tolerance were measured to detect impairment in glucose metabolism. Subsequently, the mice were treated with either MDPV (1 mg/kg) or saline, and their locomotor activity was measured. Using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), the expression of dopamine receptor D1 (Drd1), dopamine receptor D2 (Drd2), and FBJ osteosarcoma oncogene B (FosB) genes was measured in the striatum of mice.
Feeding with HFD caused obesity and glucose intolerance in mice. Restriction of fat reduced body mass and reversed impairment of glucose metabolism. HFD-fed mice responded to MDPV with higher potency than CD-fed counterparts, with an increased incidence of stereotypies. A change of diet partially reversed this effect. Downregulation of Drd2 was observed in the mice that switched from HFD to CD, whereas treatment with MDPV caused upregulation of FosB only in the CD-fed mice.
Current results suggest that obesity may increase sensitivity to psychostimulant effects of MDPV and elevate the risk of addiction as mice fed with HFD responded to acute treatment with MDPV with higher potency and showed tolerance of FosB induction in response to the drug.
本研究调查了高脂饮食对小鼠对3,4-亚甲基二氧吡咯戊酮（MDPV）急性反应的影响。MDPV是一种具有精神兴奋活性的β-卡西酮衍生物。与消遣性物质类似，美味食物的摄入会刺激中脑边缘多巴胺能系统，导致神经适应性变化。
将青春期C57BL/6N小鼠分为两组，分别喂食对照饮食（CD，脂肪提供10%的千卡热量）或高脂饮食（HFD，脂肪提供60%的千卡热量）。八周后，一组高脂饮食喂养的小鼠将饮食改为对照饮食，再持续两周。测量空腹血糖水平和葡萄糖耐量以检测葡萄糖代谢受损情况。随后，小鼠接受MDPV（1毫克/千克）或生理盐水治疗，并测量其运动活性。使用逆转录定量聚合酶链反应（RT-qPCR）测量小鼠纹状体中多巴胺受体D1（Drd1）、多巴胺受体D2（Drd2）和FBJ骨肉瘤癌基因B（FosB）基因的表达。
高脂饮食喂养导致小鼠肥胖和葡萄糖不耐受。脂肪限制可减轻体重并逆转葡萄糖代谢受损情况。高脂饮食喂养的小鼠对MDPV的反应比对照饮食喂养的小鼠更强效，刻板行为的发生率增加。饮食改变可部分逆转这种效应。从高脂饮食改为对照饮食的小鼠中观察到Drd2下调，而MDPV治疗仅在对照饮食喂养的小鼠中导致FosB上调。
当前结果表明，肥胖可能会增加对MDPV精神兴奋作用的敏感性，并增加成瘾风险，因为高脂饮食喂养的小鼠对MDPV急性治疗的反应更强效，且对药物诱导的FosB表现出耐受性。
