People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

患有抑郁症和其他神经精神疾病的人可能会出现动机功能障碍，例如疲劳和无力，这涉及到在目标导向的活动中付出的努力减少。为了模拟与努力相关的动机功能障碍，可以使用基于努力的选择任务，其中大鼠可以在通过高努力获得首选强化物与低努力/不太优选的选择之间进行选择。临床前数据表明，多巴胺转运（DAT）抑制剂可以逆转药理学引起的低努力偏差，并增加基于努力的选择任务中对高努力选项的选择。尽管可卡因等经典 DAT 阻滞剂可能会产生不良反应，例如误用和精神病反应，但并非所有 DAT 抑制剂都具有相同的神经化学特征。目前的研究通过使用两种不同的努力来表征新型 DAT 抑制剂的努力相关效应，这些抑制剂是莫达非尼类似物，具有一系列结合特征和神经化学作用（JJC8-088、JJC8-089、RDS3-094 和 JJC8-091）雄性斯普拉格-道利大鼠的相关选择行为任务。JJC8-088、JJC8-089 和 RDS3-094 显着逆转了 VMAT-2 抑制剂丁苯那嗪引起的低努力偏差，增加了高努力固定比率 5 杆按压与食物摄入的选择。此外，JJC8-089逆转了丁苯那嗪对雌性大鼠的作用。JJC8-088和JJC8-089还增加了选择任务中高努力进步比率响应的选择。然而，JJC8-091 未能产生这些结果，可能是由于其独特的药理学特征（即与 DAT 的封闭构象结合）。对具有不同神经化学特征的多种 DAT 抑制剂进行评估可能会鉴定出可用于治疗人类动机功能障碍的化合物。