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.

中文翻译：

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DAT 和 sigma 受体双重抑制剂可减弱可卡因对大鼠伏核多巴胺动力学的影响

精神兴奋剂使用障碍（PSUD）很普遍；然而，目前还没有 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）和西格玛受体的双重抑制剂可显着降低可卡因的行为/强化作用，这与 DAT 抑制引起的细胞外多巴胺（DA）水平的刺激有关。在这里，我们采用微透析和快速扫描循环伏安法 (FSCV) 程序来研究 DAT 和 sigma 受体双重抑制剂与可卡因组合对幼稚雄性 Sprague Dawley 大鼠伏核壳 (NAS) DA 动力学的影响。在微透析研究中，给予 rimcodium（3、10 mg/kg；ip）或其结构类似物 SH 3-24（1、3 mg/kg；ip）（DAT 和 sigma 受体双重抑制剂）可显着降低 NAS通过增加可卡因剂量（0.1、0.3、1.0 mg/kg；静脉注射）刺激 DA 流出。使用相同的实验条件，在 FSCV 测试中，我们发现利马唑预处理减弱了可卡因诱导的 NAS DA 释放刺激，但对 DA 清除率没有产生额外影响。在相同条件下，JJC8-091（一种莫达非尼类似物、DAT 和 sigma 受体的双重抑制剂）同样减弱了可卡因诱导的 NAS DA 释放刺激，但对 DA 清除率没有产生额外影响。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，DA 动力学可能介导可卡因等精神兴奋剂的行为效应。