Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Addict Biol. 2014 Jan;19(1):49-60. doi: 10.1111/j.1369-1600.2012.00506.x. Epub 2012 Sep 27.
Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties.
莫达非尼可能对治疗兴奋剂滥用有用，但目前尚不清楚其作用机制。事实上，莫达非尼的主要作用是抑制多巴胺转运，而多巴胺转运通常会促进而不是抑制动机行为。因此，我们研究了伏隔核细胞外谷氨酸和 II 型代谢型谷氨酸受体（mGluR2/3）在莫达非尼作用中的作用。一组大鼠接受可卡因自我给药 10 天并被消除，然后给予可卡因引发药物重新出现的引发注射。莫达非尼（300mg/kg，腹腔内注射）抑制了可卡因的重新出现寻求（但本身不会改变消除反应），而这种作用被伏隔核核心双侧 mGluR2/3 拮抗剂 LY-341495（LY）预处理所阻止。单侧伏隔核核心 LY 或双侧伏隔核头极的 LY 没有逆转莫达非尼的作用。接下来，我们试图探索莫达非尼对慢性可卡因后伏隔核细胞外谷氨酸水平的影响。单独的大鼠给予非条件性可卡因，在 3 周戒断后进行伏隔核微透析。莫达非尼增加了慢性可卡因暴露大鼠伏隔核中的细胞外谷氨酸，但对慢性盐水预处理的动物没有影响。胱氨酸-谷氨酸交换或电压依赖性钙通道拮抗剂的反向透析阻止了这种增加。电压依赖性钠通道阻断部分减弱了谷氨酸的增加，但 mGluR1 阻断没有。我们得出结论，莫达非尼从暴露于可卡因的大鼠的胶质和神经元来源中增加了伏隔核中的细胞外谷氨酸，这可能对其 mGluR2/3 介导的抗复发特性很重要。
