Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Exp Clin Psychopharmacol. 2010 Oct;18(5):395-408. doi: 10.1037/a0021042.
Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2-32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained (0.001-0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment.
莫达非尼是一种中枢神经系统兴奋剂，用于促进觉醒，目前正在临床评估作为一种治疗兴奋剂滥用的激动剂药物。这是首例关于莫达非尼对非人类灵长类动物可卡因滥用相关效应影响的报告。在三项研究中检查了莫达非尼的行为效应。首先，用训练猕猴（猕猴）来评估莫达非尼（3.2-32mg/kg）的辨别刺激效应，使其辨别低（0.18mg/kg，IM）或高（0.4mg/kg，IM）剂量的可卡因与生理盐水。莫达非尼在 7 只猴子中的 6 只中剂量依赖性替代了可卡因。在第二项研究中，研究了慢性给予莫达非尼（32-56mg/kg/天，IV）对食物和可卡因维持（0.001-0.1mg/kg/次）操作性反应的影响。莫达非尼每天 3 次/小时给药 23 小时，以确保稳定的药物水平。慢性 32mg/kg/天莫达非尼治疗选择性降低了由中等和峰值强化剂量可卡因维持的反应，但不受更高剂量可卡因维持的反应不受影响。在慢性莫达非尼治疗期间，食物维持的行为没有改变。在第三项研究中，在复吸模型中检查了莫达非尼（32 和 56mg/kg/天，IV）。莫达非尼在消退期间短暂地增加了反应。这些发现表明，莫达非尼与可卡因具有相似的辨别刺激效应，并选择性地降低了由强化剂量可卡因维持的反应。此外，莫达非尼重新引发了可卡因寻求行为，这可能反映了其类似可卡因的辨别刺激效应。这些数据支持临床发现，并表明这些临床前模型可能有助于预测激动剂药物治疗药物滥用的有效性。
