Wuo-Silva Raphael, Fukushiro-Lopes Daniela F, Fialho Bruno P, Hollais André W, Santos-Baldaia Renan, Marinho Eduardo A V, Mári-Kawamoto Elisa, Yokoyama Thaís S, Lopes-Silva Leonardo B, Berro Laís F, Frussa-Filho Roberto, Longo Beatriz M
Laboratory of Neurophysiology, Department of Physiology, Universidade Federal de São Paulo, São Paulo, Brazil.
Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.
Front Pharmacol. 2019 Mar 11;10:211. doi: 10.3389/fphar.2019.00211. eCollection 2019.
Studies on the abuse potential of modafinil, a psychostimulant-like drug used to treat narcolepsy, are still controversial. While some studies claim no potential for abuse, increasing evidence suggests that modafinil induces abuse-related effects, including rapid-onset behavioral sensitization (i.e., a type of sensitization that develops within hours from the drug priming administration). The rapid-onset sensitization paradigm is a valuable tool to study the neuroplastic changes that occur quickly after drug administration, and shares neuroadaptations with drug abuse in humans. However, the mechanisms involved in the rapid-onset behavioral sensitization induced by modafinil are uncertain. Our aim was to investigate the possible involvement of dopamine D1 and D2 receptors on acute modafinil-induced hyperlocomotion and on the induction and expression of rapid-onset behavioral sensitization induced by modafinil in male Swiss mice. Treatment with the D1 receptor antagonist SCH 23390 or the D2 receptor antagonist sulpiride attenuated the acute modafinil-induced hyperlocomotion in a dose-dependent manner. Pretreatment with either antagonist before the priming injection of modafinil prevented the development of sensitization in response to a modafinil challenge 4 h later. However, only SCH 23390 decreased the expression of modafinil-induced rapid-onset behavioral sensitization. Taken together, the present findings provide evidence of the participation of D1 and D2 receptors on the development of rapid-onset behavioral sensitization to modafinil, and point to a prominent role of D1 receptors on the expression of this phenomenon.
莫达非尼是一种用于治疗发作性睡病的类精神兴奋药物，对其滥用可能性的研究仍存在争议。虽然一些研究称其没有滥用潜力，但越来越多的证据表明，莫达非尼会引发与滥用相关的效应，包括快速发作的行为敏化（即一种在药物初次给药后数小时内就会出现的敏化类型）。快速发作敏化范式是研究药物给药后迅速发生的神经可塑性变化的宝贵工具，并且与人类药物滥用存在神经适应性变化。然而，莫达非尼诱导快速发作行为敏化所涉及的机制尚不清楚。我们的目的是研究多巴胺D1和D2受体在雄性瑞士小鼠中对急性莫达非尼诱导的运动亢进以及对莫达非尼诱导的快速发作行为敏化的诱导和表达可能产生的影响。用D1受体拮抗剂SCH 23390或D2受体拮抗剂舒必利进行治疗，可剂量依赖性地减弱急性莫达非尼诱导的运动亢进。在初次注射莫达非尼之前用任一拮抗剂进行预处理，可防止4小时后对莫达非尼激发产生敏化。然而，只有SCH 23390降低了莫达非尼诱导的快速发作行为敏化的表达。综上所述，目前的研究结果提供了证据，证明D1和D2受体参与了对莫达非尼快速发作行为敏化的形成，并且表明D1受体在这一现象的表达中起重要作用。
