Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Neuropharmacology. 2021 Dec 1;200:108786. doi: 10.1016/j.neuropharm.2021.108786. Epub 2021 Sep 10.
Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the DR/5HTR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, and this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action.
冲动行为可以定义为无法抑制反应，是广泛的冲动特质的一个维度。在这里，我们描述了我们实验室开发的一种改良的低频应答率区分强化（DRL）任务，该任务用于测量自由进食/饮水的动物的冲动行为。具体来说，我们首先通过系统比较雄性和发情同步化的雌性动物，确定了性别和发情周期对冲动行为的影响。此外，我们通过测试 DR/5HTR 拮抗剂阿立哌唑和非竞争性 NMDA 受体拮抗剂 MK-801 的作用，评估了这种改良的 DRL 任务的收敛有效性。最后，我们使用这种改良的 DRL 任务测试了 Sigma-1 受体（Sig-1R）的选择性拮抗剂 BD-1063 和激动剂 PRE-084 对冲动行为的影响。我们发现，与雄性相比，雌性大鼠表现出更难以抑制反应的能力，这种效应是由发情周期的间情期/动情前期驱动的。此外，阿立哌唑和 MK-801 完全保留了它们分别减少和增加冲动行为的能力。最后，选择性 Sig-1R 拮抗剂 BD-1063 以剂量依赖的方式减少了两性动物的无法抑制反应，而在雌性大鼠中更为显著。总之，我们表明，在一种改良的 DRL 任务中测量的冲动行为，该任务最大限度地减少了能量平衡的影响，是性别和发情周期的共同作用。此外，我们验证了该任务的收敛有效性，并提供了证据表明 Sig-1R 拮抗可能代表一种减少冲动行为的新型药理学策略。
