Higgins Guy A, Silenieks Leo B, MacMillan Cam, Thevarkunnel Sandy, Parachikova Anna I, Mombereau Cedric, Lindgren Hanna, Bastlund Jesper F
Intervivo Solutions, Toronto, ON, Canada.
Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
Front Pharmacol. 2020 Apr 24;11:427. doi: 10.3389/fphar.2020.00427. eCollection 2020.
Amphetamine (AMP), methylphenidate (MPH), and atomoxetine (ATX) are approved treatments for ADHD, and together with nicotine (NIC), represent pharmacological agents widely studied on cognitive domains including attention and impulsive action in humans. These agents thus represent opportunities for clinical observation to be reinvestigated in the preclinical setting, i.e., reverse translation. The present study investigated each drug in male, Long Evans rats trained to perform either (1) the five-choice serial reaction time task (5-CSRTT), (2) Go/NoGo task, or (3) a progressive ratio (PR) task, for the purpose of studying each drug on attention, impulsive action and motivation. Specific challenges were adopted in the 5-CSRTT designed to tax attention and impulsivity, i.e., high frequency of stimulus presentation (sITI), variable reduction in stimulus duration (sSD), and extended delay to stimulus presentation (10-s ITI). Initially, performance of a large (> 80) cohort of rats in each task variant was conducted to examine performance stability over repeated challenge sessions, and to identify subgroups of "high" and "low" attentive rats (sITI and sSD schedules), and "high" and "low" impulsives (10-s ITI). Using an adaptive sequential study design, the effects of AMP, MPH, ATX, and NIC were examined and contrasting profiles noted across the tests. Both AMP (0.03-0.3 mg/kg) and MPH (1-6 mg/kg) improved attentional performance in the sITI but not sSD or 10-s ITI condition, NIC (0.05-0.2 mg/kg) improved accuracy across all conditions. ATX (0.1-1 mg/kg) detrimentally affected performance in the sITI and sSD condition, notably in "high" performers. In tests of impulsive action, ATX reduced premature responses notably in the 10-s ITI condition, and also reduced false alarms in Go/NoGo. Both AMP and NIC increased premature responses in all task variants, although AMP reduced false alarms highlighting differences between these two measures of impulsive action. The effect of MPH was mixed and appeared baseline dependent. ATX reduced break point for food reinforcement suggesting a detrimental effect on motivation for primary reward. Taken together these studies highlight differences between AMP, MPH, and ATX which may translate to their clinical profiles. NIC had the most reliable effect on attentional accuracy, whereas ATX was reliably effective against all tests of impulsive action.
苯丙胺（AMP）、哌甲酯（MPH）和托莫西汀（ATX）是已获批准的治疗注意力缺陷多动障碍（ADHD）的药物，它们与尼古丁（NIC）一起，代表了在包括人类注意力和冲动行为在内的认知领域得到广泛研究的药理学药物。因此，这些药物为在临床前环境中重新研究临床观察提供了机会，即反向翻译。本研究在经过训练以执行以下任务之一的雄性朗·埃文斯大鼠中研究了每种药物：（1）五选择连续反应时任务（5-CSRTT）、（2）Go/NoGo任务或（3）渐进比率（PR）任务，目的是研究每种药物对注意力、冲动行为和动机的影响。在5-CSRTT中采用了特定的挑战措施，旨在考验注意力和冲动性，即高刺激呈现频率（sITI）、刺激持续时间的可变缩短（sSD）以及刺激呈现的延长延迟（10秒ITI）。最初，对每个任务变体中的一大群（>80只）大鼠的表现进行了测试，以检查重复挑战阶段的表现稳定性，并识别出“高”和“低”注意力大鼠（sITI和sSD方案）以及“高”和“低”冲动性大鼠（10秒ITI）的亚组。采用适应性序贯研究设计，研究了AMP、MPH、ATX和NIC的作用，并在各项测试中注意到了不同的特征。AMP（0.03 - 0.3毫克/千克）和MPH（1 - 6毫克/千克）在sITI条件下改善了注意力表现，但在sSD或10秒ITI条件下未改善；NIC（0.05 - 0.2毫克/千克）在所有条件下均提高了准确性。ATX（0.1 - 1毫克/千克）在sITI和sSD条件下对表现有不利影响，在“高”表现者中尤为明显。在冲动行为测试中，ATX在10秒ITI条件下显著减少了过早反应，并且在Go/NoGo任务中也减少了误报。AMP和NIC在所有任务变体中均增加了过早反应，尽管AMP减少了误报，突出了这两种冲动行为测量方法之间的差异。MPH的效果不一，似乎取决于基线。ATX降低了食物强化的断点，表明对初级奖励动机有不利影响。综合这些研究突出了AMP、MPH和ATX之间的差异，这些差异可能转化为它们的临床特征。NIC对注意力准确性的影响最为可靠，而ATX在所有冲动行为测试中均有可靠效果。
