Adam C Mar1,2,3,4, Simon R O Nilsson5,6,7,8, Begoña Gamallo-Lana5,6,7,8, Ming Lei7,8,9, Theda Dourado7,8, Johan Alsiö7,8,10, Lisa M Saksida7,8,11,12,13, Timothy J Bussey7,8,11,12,13, Trevor W Robbins7,8. 1. Neuroscience Institute, New York University Medical Center, New York, NY, 10016, USA. adam.mar@nyumc.org. 2. Department of Neuroscience and Physiology, New York University Medical Center, New York, NY, USA. adam.mar@nyumc.org. 3. Department of Psychology, University of Cambridge, Cambridge, UK. adam.mar@nyumc.org. 4. MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. adam.mar@nyumc.org. 5. Neuroscience Institute, New York University Medical Center, New York, NY, 10016, USA. 6. Department of Neuroscience and Physiology, New York University Medical Center, New York, NY, USA. 7. Department of Psychology, University of Cambridge, Cambridge, UK. 8. MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. 9. Department of Health Industry Management, Beijing International Studies University, 1 Dingfuzhuang Nanli, Beijing, China. 10. Department of Neuroscience, Unit of Functional Neurobiology, University of Uppsala, Uppsala, Sweden. 11. Molecular Medicine Research Group, Robarts Research Institute, Western University, London, ON, Canada. 12. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. 13. The Brain and Mind Institute, Western University, London, ON, Canada.
Abstract
RATIONALE: Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. OBJECTIVES: We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. METHODS: MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. RESULTS: Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. CONCLUSION: The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.
RATIONALE: Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. OBJECTIVES: We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. METHODS: MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. RESULTS: Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. CONCLUSION: The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.
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