MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

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.

Keywords: ADHD; Animal model; Attention; Behavioral pharmacology; Executive function; MAM-E17; Schizophrenia; Touch screen.

Fig. 1

Trial structure of the rCPT and timeline of drug administration for the two cohorts of MAM-E17 and sham control rats. a Schematic diagram of the trial structure of the rCPT. Each session consists of a series of trials. Each trial begins (see Trial Starts box) with a variable inter-stimulus interval (ISI) = 3–7 s in which no stimuli are present. A response to the screen during the ISI is coded as an ISI touch and reinitiates the ISI. Following the complete ISI, either a designated target stimulus (S+) or one of four nontarget stimuli (S–) is presented individually within a central response window on a touch-sensitive monitor. Each stimulus is programmed to have a variable stimulus duration (SD) = 0.5–1.5 s. On normal trials, if an S+ is displayed, a touch to the response window during a limited hold period following stimulus onset (LH = 2 s) is classified as a hit and leads to removal of the visual stimulus and reward delivery. Following reward collection, the normal-trial ISI prior to the next stimulus is initiated after a brief ingestion delay (ID) = 5 s that affords the animal time to consume the reward. Failure to respond to the S+ stimulus within the LH is recorded as a miss and initiates the next normal-trial ISI. If an S– is displayed, omitting a response within the LH is classified as a correct rejection and initiates the next normal-trial ISI. A response-window touch during the LH of S– presentation is classified as a false alarm and causes removal of the visual stimulus and onset of a correction-trial ISI. Correction trials—in which a randomly selected S– is presented—are repeated until a successful correct rejection is completed. b Timeline illustrating the order of the drug administration studies in cohorts 1 and 2 of MAM-E17 and sham control rats

Fig. 2

rCPT acquisition data and long-term stability of baseline task performance in MAM-E17 and sham control animals. a Stage 1 no differences between MAM-E17 and sham groups on the number of sessions to criterion. b Stage 2 no differences between MAM-E17 and sham groups on mean hit rate. c Stage 3 no differences between MAM-E17 and sham animals on performance sensitivity, d′, averaged across the last 3 days of testing. d Stage 4 mean d′ in the rCPT at four baseline time points for cohorts 1 and 2. Each time point comprises two to three sessions prior to commencing a Latin square drug study. MAM-E17 rats show stable deficits in d′ across the four time points spanning several months. There were no significant effects of cohort or cohort × group interactions. Data are expressed as mean ± SEM. Hash tags denote significant main effects of group (^# p < 0.05; ^## p < 0.01)

Fig. 3

Effect of sulpiride, atomoxetine, LSN2463359, and RO4938581 on rCPT performance in MAM-E17 and sham control rats. All significant group differences are relative to sham controls, and significant drug effects are in comparison to the vehicle treatment. For all compounds, MAM-E17 rats exhibited a dose-independent decrease in d′ relative to shams (a, c, e, g) a, b Sulpiride. a Sulpiride (30 mg/kg) increased response criterion (c) in MAM-E17 animals without affecting d′. b Sulpiride (30 mg/kg) reduced the elevated FAR selectively in MAM-E17 animals and caused reductions in HR and ISI touches across both MAM-E17 and sham animals. c, d Atomoxetine. c Atomoxetine increased c at both 0.3 and 1.0 mg/kg doses and reduced d′ at a 1.0 mg/kg dose. d Atomoxetine decreased HR and d′ at 0.3 and 1.0 mg/kg and reduced FAR at 1.0 mg/kg. MAM-E17 animals showed a dose-independent increase in FAR relative to shams. e, f LSN2463359. e LSN2463359 (5 mg/kg) increased c across both groups of animals. MAM-E17 animals showed a dose-independent decrease in d′ compared to shams. f LSN2463359 (5 mg/kg) reduced HR and ISI touches in both MAM-E17 and sham groups. MAM-E17 animals showed a dose-independent increase in FAR. g, h RO4938581. g RO4938581 (10 mg/kg) increased c in both groups of rats. MAM-E17 animals showed a dose-independent decrease in d′ relative to sham controls. h RO4938581 (10 mg/kg) decreased HR, FAR, and ISI touches in both groups. MAM-E17 animals showed a dose-independent increase in FAR compared to sham controls. Gray shading with asterisks denotes the main effect of drug dose with a significant difference from vehicle. Red shading with asterisks denotes group × dose interaction with a significant difference from vehicle (*p < 0.05; **p < 0.01; ***p < 0.0001). Hash tags denote significant main effects of group (^# p < 0.05; ^## p < 0.01; ^### p < 0.0001)

Fig. 4

Effect of modafinil and ABT-594 on rCPT performance in sham and MAM-E17-treated rats. All significant group differences are relative to sham controls, and significant drug effects are in comparison to the vehicle treatment. a, b. Modafinil. a At 8 mg/kg, modafinil increased d′ selectively in the sham group without affecting d′ in MAM-E17 animals. At 64 mg/kg, modafinil decreased d′ and response criterion (c) across both groups. b At 64 mg/kg, modafinil increased FAR and ISI touches and in both groups. c, d ABT-594. c ABT-594 caused group-independent decreases in c at both 5.9 and 19.4 μg/kg doses. MAM-E17 animals showed dose-independent reductions in d′ relative to controls. d ABT-594 (19.4 μg/kg) also increased FAR, HR, and ISI touches in both groups. MAM animals showed dose-independent increases in FAR and ISI touches. Gray shading with asterisks denotes the main effect of drug dose with a significant difference from vehicle. Red shading with asterisks denotes group × dose interaction with a significant difference from vehicle (*p < 0.05; **p < 0.01; ***p < 0.0001). Hash tags denote significant main effects of group (^# p < 0.05; ^### p < 0.0001)

Fig. 5

Effect of donepezil and EVP-6124 on rCPT performance in sham and MAM-E17-treated rats. a, b Donepezil. a There was a near-significant improvement in d′ by donepezil (0.1 mg/kg) across both groups of animals. MAM-E17 animals exhibited dose-independent decreases in d′. b No effects of EVP-6124 on HR, FAR, or ISI touches. MAM-E17 animals showed a dose-independent increase in FAR. c, d. EVP-6124. c, d No effects of EVP-6124 on any principal rCPT performance indices. Gray-shaded asterisk denotes the main effect of drug dose with a significant difference from vehicle. Hash tags denote a significant main effect of group (^# p < 0.05; ^## p < 0.01)