Abstract
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.
Highlights
Limitations to the translation of preclinical findings to the clinic has been a longstanding issue which has lead some to question the value of animal models in therapeutic areas such as psychiatry where etiology is generally considered to be poorly understood (Kola and Landis, 2004; Littman and Williams, 2005; Enna and Williams, 2009; van der Worp et al, 2010)
A total of 106 rats were run in this task and a meta-analysis of data from all rats is presented in Figures 1A–C and Table 1
Performance of rats in this test variant demonstrated the challenge of shortening the ITI with accuracy, response speed, and omissions showing a reliable decline as the ITI decreased from 5 s to 3.5 s to 2 s
Summary
Limitations to the translation of preclinical findings to the clinic has been a longstanding issue which has lead some to question the value of animal models in therapeutic areas such as psychiatry where etiology is generally considered to be poorly understood (Kola and Landis, 2004; Littman and Williams, 2005; Enna and Williams, 2009; van der Worp et al, 2010). One reaction to this view has been to place emphasis on translational research where animal tests are designed to align closely to those conducted in humans, and to design early phase human tests taking features from existing animal tests. Complex clinical disorders can be fractionated into discrete symptom clusters which may be more amenable to translational research and treatment (Pangalos et al, 2007; Day et al, 2008; Miczek and de Wit, 2008; Markou et al, 2009; McArthur, 2017)
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