Rotolo Renee A, Dragacevic Vladimir, Kalaba Predrag, Urban Ernst, Zehl Martin, Roller Alexander, Wackerlig Judith, Langer Thierry, Pistis Marco, De Luca Maria Antonietta, Caria Francesca, Schwartz Rebecca, Presby Rose E, Yang Jen-Hau, Samels Shanna, Correa Merce, Lubec Gert, Salamone John D
Department of Psychological Sciences, University of Connecticut, Storrs, CT, United States.
Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
Front Pharmacol. 2019 Jun 28;10:682. doi: 10.3389/fphar.2019.00682. eCollection 2019.
Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. -CE-123 (--((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of -CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. -CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that -CE-123 significantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, -CE-123 has the behavioral and neurochemical profile of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that -CE-123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans.
基于努力的选择行为的动物研究正被用于模拟人类与努力相关的动机功能障碍。通过这些程序，为动物提供了两种选择：一种是导致高价值强化物的高努力工具性行动，另一种是低努力/低奖励选项。先前的几项研究表明，多巴胺（DA）摄取抑制剂，包括GBR12909、赖氨酸安非他命、哌醋甲酯和PRX - 14040，可以逆转囊泡单胺转运阻滞剂丁苯那嗪的与努力相关的效应，丁苯那嗪会抑制DA的储存。由于许多阻断DA转运的药物作为主要兴奋剂也会释放DA，并产生许多不良副作用，因此需要开发和表征新型非典型DA转运抑制剂。-CE - 123（--((二苯甲基亚磺酰基)甲基)噻唑）是最近开发的一种莫达非尼类似物，具有非典型DA转运阻滞剂的生化特性。本文描述了-CE - 123的对映选择性合成和初步化学表征，以及涉及基于努力的选择的行为实验和细胞外DA的微透析研究。使用固定比率5/食物喂养选择测试对大鼠进行评估。丁苯那嗪（1.0 mg/kg）改变了选择行为，减少了杠杆按压并增加了食物摄入量。-CE - 123以6.0至24.0 mg/kg的剂量共同给药，最高剂量部分但显著地逆转了丁苯那嗪的效应，尽管该剂量单独给药时对固定比率反应没有影响。额外的实验表明，-CE - 123在渐进比率/食物喂养选择任务中显著增加了杠杆按压，并且有效剂量（24.0 mg/kg）增加了伏隔核核心中的细胞外DA。总之，-CE - 123具有一种化合物的行为和神经化学特征，该化合物可以阻断DA转运，逆转丁苯那嗪的与努力相关的效应，并增加对高努力渐进比率反应的选择。这表明-CE - 123或类似化合物可能作为治疗人类与努力相关的动机功能障碍的药物有用。
