Department of Pharmacology and Therapeutic Chemistry, Pharmacology Section and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Department of Pharmacology and Therapeutic Chemistry, Pharmacology Section and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Biochem Pharmacol. 2019 May;163:84-93. doi: 10.1016/j.bcp.2019.02.004. Epub 2019 Feb 6.
3,4-Methylenedioxypyrovalerone (MDPV) acts as a dopamine transporter blocker and exerts powerful psychostimulant effects. In this study we aimed to investigate the bidirectional cross-sensitization between MDPV and cocaine, as well as to evaluate the role of the BDNF-TrkB signaling pathway in the development of locomotor sensitization to both drugs. Mice were treated with MDPV (1.5 mg/kg) or cocaine (10 or 15 mg/kg) once daily for 5 days. After withdrawal (10 days), animals were challenged with cocaine (8 mg/kg) or MDPV (1 mg/kg). For biochemical determinations, MDPV (1.5 mg/kg) or cocaine (15 mg/kg) were administered acutely or repeatedly, and BDNF, D3R and G9a transcription levels as well as pro- and mature BDNF protein levels were determined. Our results demonstrate that repeated administration of MDPV or cocaine sensitizes to cocaine and MDPV locomotor effects. After an acute or a repeated exposure to MDPV, cortical mRNA BDNF levels were increased, while a decrease in mBDNF protein levels in the nucleus accumbens 2 h after repeated exposure was evidenced. Interestingly, such decline was involved in the development of locomotor sensitization, thus the pretreatment with 7,8-dihydroxyflavone (10 mg/kg), a TrkB agonist, blocked the development of sensitization to MDPV but not to cocaine, for which no changes in the BDNF-TrkB signaling pathway were observed at early withdrawal. In conclusion, a bidirectional cross-sensitization between MDPV and cocaine was evidenced. Our findings suggest that decreased BDNF-TrkB signaling has an important role in the behavioral sensitization to MDPV, pointing TrkB modulation as a target to prevent MDPV sensitization.
3,4-亚甲二氧基吡咯戊酮（MDPV）作为一种多巴胺转运体阻断剂，发挥强大的精神兴奋剂作用。本研究旨在探讨 MDPV 和可卡因之间的双向交叉敏感化，以及 BDNF-TrkB 信号通路在两种药物引起的运动敏化中的作用。小鼠每天接受 MDPV（1.5mg/kg）或可卡因（10 或 15mg/kg）治疗一次，共 5 天。停药（10 天后）后，动物接受可卡因（8mg/kg）或 MDPV（1mg/kg）挑战。为了进行生化测定，急性或重复给予 MDPV（1.5mg/kg）或可卡因（15mg/kg），并测定 BDNF、D3R 和 G9a 的转录水平以及 pro-和成熟 BDNF 蛋白水平。结果表明，重复给予 MDPV 或可卡因可使可卡因和 MDPV 的运动效应敏感化。急性或重复暴露于 MDPV 后，皮质 mRNA BDNF 水平增加，而重复暴露 2 小时后，伏隔核中的 mBDNF 蛋白水平下降。有趣的是，这种下降参与了运动敏化的发展，因此，用 TrkB 激动剂 7,8-二羟基黄酮（10mg/kg）预处理可阻断对 MDPV 的敏化，但对可卡因没有影响，因为在早期停药时，BDNF-TrkB 信号通路没有观察到变化。综上所述，证明了 MDPV 和可卡因之间存在双向交叉敏感化。我们的研究结果表明，BDNF-TrkB 信号的减少在对 MDPV 的行为敏化中起着重要作用，提示 TrkB 调节作为预防 MDPV 敏化的靶点。
