Effects of methylphenidate on attentional set-shifting in a genetic model of attention-deficit/hyperactivity disorder

Abstract

Background: Although deficits of attentional set-shifting have been reported in individuals with attention deficit/hyperactivity disorder (ADHD), it is rarely examined in animal models.

Methods: This study compared spontaneously hypertensive rats (SHRs; a genetic animal model of ADHD) and Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (normoactive control strains), on attentional set-shifting task (ASST) performance. Furthermore, the dose-effects of methylphenidate (MPH) on attentional set-shifting of SHR were investigated. In experiment 1, ASST procedures were conducted in SHR, WKY and SD rats of 8 each at the age of 5 weeks. Mean latencies at the initial phase, error types and numbers, and trials to criteria at each stage were recorded. In experiment 2, 24 SHR rats were randomly assigned to 3 groups of 8 each-- MPH-L (lower dose), MPH-H (higher dose), and SHR-vehicle groups. From 3 weeks, they were administered 2.5 mg/kg or 5 mg/kg MPH or saline respectively for 14 consecutive days. All rats were tested in the ASST at the age of 5 weeks.

Results: The SHRs generally exhibited poorer performance on ASST than the control WKY and SD rats. Significant strain effects on mean latency [F (2, 21) = 639.636, p < 0.001] and trials to criterion [F (2, 21) = 114.118, p < 0.001] were observed. The SHRs were found to have more perseverative and regressive errors than the control strains (p < 0.001). After MPH treatment, the two MPH treated groups exhibited significantly longer latency and fewer trials to reach criterion than the SHR-vehicle group and the MPH-L group exhibited fewer trials to reach criterion in more stages compared with the MPH-H group. Significant main effects of treatment [F (2, 21) = 52.174, p < 0.001] and error subtype [F (2, 42) = 221.635, p < 0.01] were found.

Conclusions: The SHR may be impaired in discrimination learning, reversal learning and attentional set-shifting. Our study provides evidence that MPH may improve the SHR's performance on attentional set-shifting and lower dose is more effective than higher dose.

Figure 1

Strain comparison of the mean latency (A), and the number of trials to criterion (B) for each of the stage during the training. (C) Analysis of the subtypes of errors made by three rats during the whole task. Values are expressed as mean ± SEM accuracy measured in spontaneous hypertensive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley (SD) strains. *p < 0.05,**p < 0.01 when compared with SHR rats. #p < 0.01 compared in CD and ID, ID and ED.

Figure 2

Effects of treatment with low-dose methylphenidate (2.5 mg/kg) and high-dose methylphenidate (5 mg/kg) on spontaneous hypertensive rat (SHR) strains on the mean latency (A), the number of trials to criterion (B) and the analysis of the subtypes of errors (C) during the attentional set-shifting task. Values are expressed as mean ± SEM *P < 0.05, **P < 0.01 when compared with vehicle-treated controls. #p < 0.01: compared in CD and ID, ID and ED,⋆p < 0.01: compared in MPH-H and MPH-L.