Behavioural Neuroscience Laboratory, Mental Health Research Institute, Parkville, Melbourne, Australia.
Eur J Pharmacol. 2013 Jan 15;699(1-3):132-40. doi: 10.1016/j.ejphar.2012.11.041. Epub 2012 Dec 5.
Modafinil is a wakefulness-promoting agent with possible beneficial effects for the management of addiction and in psychiatric conditions, but also with abuse potential of its own. The mechanism of action of modafinil remains unclear. We studied pharmacological mechanisms in the effect of modafinil on prepulse inhibition (PPI), a model of sensorimotor gating. Mice were tested in automated startle boxes after administration of modafinil and antagonist drugs. Oral administration of 100mg/kg of modafinil, but not lower doses, caused a significant reduction of PPI in C57Bl/6 mice, but not Balb/c mice. This effect of modafinil could be blocked by co-treatment with the dopamine D(2) receptor antagonist, haloperidol, and the serotonin (5-HT) 2A receptor antagonist, ketanserin, but not the 5-HT(1A) receptor antagonist, WAY100,635. At 30mg/kg, which did not influence PPI, modafinil inhibited PPI disruption caused by the dopamine transporter inhibitor, GBR12909. There was no interaction between modafinil and the serotonin transporter inhibitor, fluoxetine. There were no consistent effects of modafinil on startle amplitude. These results show that oral modafinil treatment may cause disruption of PPI in mice. This effect was strain-dependent, involving dopamine D(2) and 5-HT(2A) receptor activation, and was likely mediated by an interaction with the dopamine transporter. These results extend our insight into the behavioral effects of modafinil and could be of importance for the clinical use of this agent as they may indicate an increased risk of side-effects in conditions where PPI is already reduced, such as in schizophrenia and bipolar disorder.
莫达非尼是一种促醒药物，可能对成瘾和精神疾病的治疗有益，但也有其自身的滥用潜力。莫达非尼的作用机制尚不清楚。我们研究了莫达非尼对条件性回避反应（PPI）的影响中的药理学机制，PPI 是一种感觉运动门控模型。在给予莫达非尼和拮抗剂药物后，用自动惊跳箱测试小鼠。口服 100mg/kg 的莫达非尼，但不是更低的剂量，可导致 C57Bl/6 小鼠的 PPI 显著降低，但 Balb/c 小鼠则没有。莫达非尼的这种作用可以通过与多巴胺 D2 受体拮抗剂氟哌啶醇和 5-羟色胺（5-HT）2A 受体拮抗剂酮色林共同治疗来阻断，但不能通过 5-HT1A 受体拮抗剂 WAY100,635 来阻断。在不影响 PPI 的 30mg/kg 剂量下，莫达非尼抑制了多巴胺转运蛋白抑制剂 GBR12909 引起的 PPI 破坏。莫达非尼与 5-羟色胺转运蛋白抑制剂氟西汀之间没有相互作用。莫达非尼对惊跳幅度没有一致的影响。这些结果表明，口服莫达非尼治疗可能导致小鼠的 PPI 破坏。这种作用与品系有关，涉及多巴胺 D2 和 5-HT2A 受体的激活，可能是通过与多巴胺转运蛋白的相互作用介导的。这些结果扩展了我们对莫达非尼行为作用的认识，可能对该药物的临床应用很重要，因为它们可能表明在 PPI 已经降低的情况下，如精神分裂症和双相情感障碍，副作用的风险增加。
