ADHD medication and the inverted U-shaped curve: A pharmacological study in female mice performing the rodent Continuous Performance Test (rCPT).

BACKGROUND: The rodent Continuous Performance Test (rCPT) is an analogue of human CPTs where mice have to discriminate between target and non-target stimuli. The rCPT offers a readout of attentional performance and impulsive behaviour. This study aimed to determine if female C57BL/6 J mice could be trained in the rCPT since previously published rCPT studies have only used male mice and to study whether the effects of methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (AMPH) on attention and impulsivity depend on baseline (reference) levels of performance. METHODS: 48 female mice underwent rCPT training. Effects of MPH (1, 2, and 3 mg/kg), ATX (1, 3, and 5 mg/kg) and AMPH (0.3, 0.6, and 1 mg/kg) were assessed in a variable stimulus duration probe. Drugs were administered intraperitoneally and sequentially tested following a Latin-square design. Data were analysed using a repeated measurements mixed effect model and reference-dependent effects were studied. RESULTS: ATX and AMPH improved performance as seen by increases in discriminability. These improvements were a result of a decreased false-alarm rate. AMPH showed a reference-dependent effect, improving the task performance of low-performing mice and decreasing the performance of high-performing mice. MPH also showed this reference-dependent effects, albeit to a lesser extent. ATX and AMPH decreased premature responses and increased response criterion, but no reference-dependent effects were observed for these parameters. CONCLUSION: This study presents a novel method to analyse baseline-dependent effects. It shows that the rCPT can be successfully used in pharmacological studies in female mice and demonstrates that the effect of ADHD medication is in line with the inverted U-shape theory of performance-arousal relationship.

Effect of ADHD medication in male C57BL/6J mice performing the rodent Continuous Performance Test.

RATIONALE: The rodent Continuous Performance Test (rCPT) is a novel rodent paradigm to assess attention and impulsivity that resembles the human CPT. This task measures the rodents' ability to discriminate between target and non-target stimuli. The effect of attention-deficit/hyperactivity disorder (ADHD) medication on rCPT performance in mice remains to be fully characterized. OBJECTIVE: To investigate the predictive validity of the mouse rCPT by studying the effects of ADHD medication methylphenidate, atomoxetine, amphetamine, guanfacine, and modafinil in four behavioral subgroups based on performance and impulsivity levels. METHODS: Two cohorts of male C57BL/6J mice were used, and the effect of treatment was tested in a variable stimulus duration probe. Performance and impulsive subgroups were made based on discriminability and percentage premature responses, respectively. RESULTS: Methylphenidate, atomoxetine, and amphetamine improved performance in the low-performing animals, with no effect in the high-performers. These improvements were a result of increased hit rate and/or decreased false-alarm rate. Furthermore, these drugs decreased percentage premature responses in the high-impulsive group. Methylphenidate, guanfacine, and modafinil increased premature responses in the low-impulsive group. Modafinil impaired performance in the high-performers by increasing false-alarm rate. CONCLUSION: The effect of ADHD treatment was dependent on baseline, as seen by increases in performance for the low-performers and decreases in impulsivity for the high-impulsive animals. These results agree with clinical data and may support the inverted U-shaped arousal-performance theory. The rCPT combined with behavioral separation into subgroups has high predictive validity, and our study is a step forward towards establishing the clinical translatability of the rCPT.