MAM E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs
RationaleImpairments 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.ObjectivesWe 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.MethodsMAM 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.ResultsTwo 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 mg/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.ConclusionThe 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.
Psychopharmacology