PDF(Pubmed)
Abstract：
Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.
摘要：
精神兴奋剂使用障碍（PSUD）很普遍；然而，没有FDA批准的药物可用于治疗.先前的研究表明，多巴胺转运蛋白（DAT）和sigma受体的双重抑制剂显着降低了可卡因的行为/增强作用，与DAT抑制引起的细胞外多巴胺（DA）水平的刺激有关。这里,我们使用微透析和快速扫描循环伏安法（FSCV）程序来研究DAT和sigma受体的双重抑制剂与可卡因联合对幼稚雄性SpragueDawley大鼠伏隔核壳（NAS）DA动力学的影响。在微透析研究中，服用rimcazole（3，10mg/kg；i.p.）或其结构类似物SH3-24（1，3mg/kg；i.p.），是DAT和σ受体双重抑制剂的化合物，通过增加可卡因的剂量(0.1、0.3、1.0mg/kg;静脉内)显著降低了NASDA外排刺激。使用相同的实验条件，在FSCV测试中，我们表明，rimcazole预处理减弱了可卡因诱导的诱发NASDA释放的刺激，但对DA清除率没有额外影响。在同样的条件下,JJC8-091，一种莫达非尼类似物和DAT和sigma受体的双重抑制剂，类似地减弱了可卡因诱导的诱发NASDA释放的刺激，但对DA清除率没有其他影响。我们的结果为理解DAT和sigma受体双重抑制剂对DA动力学的作用提供了神经化学基础，这些作用可能介导可卡因等精神兴奋剂的行为作用。
