Thanos PK, Ivanov I, Robinson JK, Michaelides M, Wang GJ, Swanson JM et al. Dissociation between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats in baseline performance and methylphenidate response on measures of attention|, impulsivity and hyperactivity in a Visual Stimulus Position Discrimination Task. Pharmacol Biochem Behav94: 374-379

Laboratory of Neuroimaging, NIAAA, NIH, Dept of Health and Human Services, Bethesda, MD 20892, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 10/2009; 94(3):374-9. DOI: 10.1016/j.pbb.2009.09.019
Source: PubMed


The spontaneously hypertensive rat (SHR) is a widely accepted rodent model of Attention Deficit/Hyperactivity Disorder (ADHD), and methylphenidate (MP) is a central nervous system stimulant that has been shown to have a dose-related positive effect on attention task performance in humans with ADHD. The current study was undertaken to compare SHR to its typical control strain, Wistar-Kyoto (WKY) rats, on the performance of a Visual Stimulus Position Discrimination Task (VSPDT) as well as of the responsiveness of the two rat strains to MP treatment. The rats were initially trained on the VSPDT, in which a light cue was presented randomly at three different cue-light intervals (1s, 300ms and 100ms) over one of two levers, and presses on the lever corresponding to the light cue were reinforced with a food pellet. Once rats reached stable performance, the treatment phase of the study began, during which they received daily intraperitoneal (IP) injections of saline, 2mg/kg, 5mg/kg, and 10mg/kg of MP in a randomized order immediately prior to being tested on the VSPDT. Baseline performance accuracy on the VSPDT did not differ between the groups. Furthermore, a striking strain dissociation was evident in the response of the two strains to treatment; VSPDT performance was substantially disrupted by the 5 and 10mg/kg dose in the WKY rats but only mildly in the SHR rats. Response omissions were also increased only in WKY rats. Finally, both strains had increased locomotor activity in the operant chamber following MP treatment. These findings point to an important difference in response tendency to MP in the two strains that supports a view that a critical difference between these strains may suggest neurochemical and neuroadaptive differences associated with the behavioral impairments of ADHD.


Available from: Panayotis Thanos
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    • "The spontaneously hypertensive rat (SHR) is the most widely studied animal model of ADHD (Sagvolden 2000; Sagvolden et al. 2009). Despite the prevalent use of this strain, the majority of evidence suggests that sustained attention is not compromised in SHR (Van den Bergh et al. 2006; Thanos et al. 2010; but see Sagvolden and Xu 2008). In contrast, performance in response-withholding paradigms, such as the DRL schedule, consistently shows a reduced response inhibition capacity in SHR compared to normoactive controls (Evenden and Meyerson 1999; Ferguson et al. 2007; Orduña et al. 2009; Sagvolden and Berger 1996; Sanabria and Killeen 2008; van den Bergh et al. 2006). "
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    ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is associated with a higher prevalence of smoking, which may be related to potential therapeutic effects of nicotine on ADHD symptoms. Whereas nicotine offers robust improvements in sustained attention, the effects of nicotine on impulsivity are unclear. The present study examined the effects of nicotine on the response inhibition capacity of spontaneously hypertensive rats (SHR), an animal model of ADHD, compared to that of a normotensive control Wistar Kyoto (WKY), using the fixed minimum interval (FMI) schedule of reinforcement. Tests were conducted following acute injections of subcutaneous nicotine (0.1-0.6 mg/kg). On each FMI trial, the first lever press initiated an inter-response time (IRT); a head entry into a food receptacle terminated the IRT. IRTs longer than 6 s were intermittently reinforced with sucrose. A model that assumes that only a proportion of IRTs are sensitive to the timing contingencies of the FMI provided a close fit to the data, regardless of strain or treatment. No baseline difference in FMI performance was observed between SHR and WKY. Nicotine reduced the duration of timed IRTs and the duration of latencies to the IRT-initiating lever press similarly for both strains. Nicotine dose-dependently increased the proportion of timed IRTs; the dose-response curve was shifted leftwards in SHR relative to WKY. These results suggest that nicotine (a) reduces response-inhibition capacity, (b) enhances the reinforcing efficacy of sucrose, and (c) dose-dependently enhances attention-like sensitivity to contingencies of reinforcement, through mechanisms that are yet unknown.
    Psychopharmacology 01/2014; 231(12). DOI:10.1007/s00213-013-3412-2 · 3.88 Impact Factor
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    • "The current study used the Wistar-Kyoto rat (WKY) as the “normal” (i.e., misdiagnosed) rat, as it is the genetic control for the Spontaneously Hypertensive/Hyperactive rat (SHR). The SHR has been widely used and extensively studied as an animal model for ADHD [39] and was used as a control strain. The current longitudinal study aimed to investigate the long-term effects on cognitive and neural development of chronic MPH administration during adolescence in the rat. "
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    ABSTRACT: The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed “normal” (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in “normal” WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls.
    09/2012; 2(3):375-404. DOI:10.3390/brainsci2030375
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    • "The objective of this study is to clarify this controversy using several different rat strains in the same dose–response protocol of MPD on different sexes of adolescent rats. Since MPD is used in ADHD therapy we selected to investigate the dose–response property of MPD in an animal model for ADHDthe spontaneous hyperactive rat (SHR) [32] [33] [34] [35] [36]. The SHR strain was bred from progenitor Wistar-Kyoto (WKY) rats. "
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    ABSTRACT: Methylphenidate (MPD) is the most widely used drug in the treatment of attention-deficit hyperactivity disorder (ADHD). ADHD has a high incidence in children and can persist in adolescence and adulthood. The relation between sex and the effects of acute and chronic MPD treatment was examined using adolescent male and female rats from three genetically different strains: spontaneously hyperactive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley (SD). Rats from each strain and sex were randomly divided into a control group that received saline injections and three MPD groups that received either 0.6 or 2.5 or 10mg/kg MPD injections. All rats received saline on experimental day 1 (ED1). On ED2 to ED7 and ED11, the rats were injected either with saline or MPD and received no treatment on ED8-ED10. The open field assay was used to assess the dose-response of acute and chronic MPD administration. Significant sex differences were found. Female SHR and SD rats were significantly more active after MPD injections than their male counterparts, while the female WKY rats were less active than the male WKY rats. Dose dependent behavioral sensitization or tolerance to MPD treatment was not observed for SHR or SD rats, but tolerance to MPD was found in WKY rats for the 10mg/kg MPD dose. The use of dose-response protocol and evaluating different locomotor indices provides the means to identify differences between the sexes and the genetic strain in adolescent rats. In addition these differences suggest that the differences to MPD treatment between the sexes are not due to the reproductive hormones.
    Behavioural brain research 08/2011; 226(1):8-17. DOI:10.1016/j.bbr.2011.08.027 · 3.03 Impact Factor
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