M Caballero-Puntiverio1,2, L S Lerdrup3, M Grupe3, C W Larsen4,3, A G Dietz3,5, J T Andreasen4. 1. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. maitane.puntiverio@sund.ku.dk. 2. Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. maitane.puntiverio@sund.ku.dk. 3. Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. 4. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. 5. Center for Translational Neuromedicine, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
Abstract
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.
RATIONALE: The rodent Continuous Performance Test (rCPT) is a novel rodent paradigm to assess attention and impulsivity that resembles the humanCPT. 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.
Authors: Filip S Polli; Theis H Ipsen; Maitane Caballero-Puntiverio; Tina Becher Østerbøg; Susana Aznar; Jesper T Andreasen; Kristi A Kohlmeier Journal: Mol Neurobiol Date: 2020-01-08 Impact factor: 5.590
Authors: István Gyertyán; Jana Lubec; Alíz Judit Ernyey; Christopher Gerner; Ferenc Kassai; Predrag Kalaba; Kata Kozma; Iva Cobankovic; Gábor Brenner; Judith Wackerlig; Eva Franschitz; Ernst Urban; Thierry Langer; Jovana Malikovic; Gert Lubec Journal: Sci Rep Date: 2021-12-14 Impact factor: 4.379