Abstract
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 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.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.
Highlights
Neurological and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and Alzheimer’s disease have profiles of cognitive impairment that are critical targets for therapeutic remediation
The effect size was large, virtually identical in two cohorts of animals (Cohen’s d = 1.23 and 1.27), and consistent across repeated drug testing. This model profile is remarkably similar to impairments on common variants of human continuous performance test (CPT) widely reported in neuropsychiatric disorders such as ADHD or schizophrenia (Chen and Faraone 2000; Riccio et al 2002)
It should be noted that the present study examined stable rodent continuous performance test (rCPT) performance in middleaged, male rats to help make it comparable to previous studies examining attentional and executive performance in the methylazoxymethanol acetate (MAM)-E17 model
Summary
Neurological and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and Alzheimer’s disease have profiles of cognitive impairment that are critical targets for therapeutic remediation. Histological and electrophysiological evidence reveals structural and functional disruptions predominantly within hippocampal and frontostriatal circuitries in the MAM-E17 model (Gourevitch et al 2004; Penschuck et al 2006; Moore et al 2006; Lodge and Grace 2008; Matricon et al 2010; Hradetzky et al 2012; Gastambide et al 2012; Phillips et al 2012; Snyder et al 2012) These disruptions mirror well-established abnormalities in individuals afflicted with schizophrenia: hippocampal and cortical disorganization including aberrant expression of markers for inhibitory (Benes et al 1996; Lewis 2000) and excitatory (Deakin et al 1989; Tsai et al 1995) signaling efficacy and striatal dopamine (DA) hyperfunction (Abi-Dargham et al 2000)
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