Korotkova T M, Klyuch B P, Ponomarenko A A, Lin J S, Haas H L, Sergeeva O A
Department of Neurophysiology, Heinrich-Heine-Universität, Universitätstrasse 1, D-40001 Düsseldorf, Germany.
Neuropharmacology. 2007 Feb;52(2):626-33. doi: 10.1016/j.neuropharm.2006.09.005. Epub 2006 Oct 30.
Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficit disorder, cocaine dependence and as an adjunct to antidepressants with low propensity for abuse. We investigated the modafinil action on identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices. Modafinil (20 microM) inhibited the firing of dopaminergic, but not GABAergic neurons. This inhibition was maintained in the presence of tetrodotoxin and was accompanied by hyperpolarization. Sulpiride (10 microM), a D2-receptor antagonist, but not prazosine (20 microM, an alpha1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptake with a low dose of nomifensine (1 microM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinil evoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells, identified by single-cell RT-PCR, which reversed polarity near the K(+) equilibrium potential and were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DA neurons through D2 receptors.
莫达非尼是一种耐受性良好的药物，可用于治疗过度嗜睡、注意力缺陷障碍、可卡因依赖，也可作为抗抑郁药的辅助药物，且滥用倾向较低。我们研究了莫达非尼对大鼠脑片腹侧被盖区（VTA）和黑质（SN）中已鉴定的多巴胺能神经元和γ-氨基丁酸能神经元的作用。莫达非尼（20微摩尔）抑制多巴胺能神经元的放电，但不抑制γ-氨基丁酸能神经元的放电。这种抑制在存在河豚毒素的情况下得以维持，并伴有超极化。舒必利（10微摩尔），一种D2受体拮抗剂，但哌唑嗪（20微摩尔，一种α1肾上腺素能受体阻滞剂）不能消除莫达非尼的作用。低剂量的诺米芬辛（1微摩尔）抑制多巴胺再摄取以舒必利依赖的方式减少了多巴胺能神经元的放电，并减弱了莫达非尼的作用。在急性分离的神经元上，莫达非尼在通过单细胞逆转录-聚合酶链反应鉴定的酪氨酸羟化酶阳性细胞中诱发了D2受体介导的外向电流，该电流在钾离子平衡电位附近极性反转，并且在存在诺米芬辛的情况下不变。因此，莫达非尼通过D2受体直接抑制多巴胺能神经元。
