Methylphenidate reduces impulsive-like behaviour in juvenile wistar rats, but not in adult SHR, WKY and wistar rats

Jean-Charles Bizot , Nicolas Chenault, Bérengère Houzé, Alexandre Herpin, Sabrina David, Stéphanie Pothion & Fabrice Trovero, (Emma J. Kidd, sponsor) Key-Obs SA, Parc Technologique de la Source, 3 allée du titane, 45100 Orléans, France.

Impulsivity is a core symptom of Attention Deficit/Hyperactivity Disorder (ADHD), which mainly affects children. The most commonly prescribed treatments for ADHD are psychostimulants, in particular methylphenidate. The Spontaneously Hypertensive Rat (SHR) is a strain commonly used as an animal model of ADHD. However, there is no clear evidence that psychostimulants reduce impulsive behaviour in SHR. The first aim of this study was to compare impulsive-related behaviour and methylphenidate effects thereon in adult rats of three strains, SHR, Wistar Kyoto (WKY) and Wistar. In addition, because psychostimulants exert similar behavioural effects in normal and hyperactive children (Rapoport et al. , 2002), the second aim of the study was to investigate whether methylphenidate affects impulsive-related behaviour in normal juvenile Wistar rats.

Since impulsive subjects are described as intolerant to delay of gratification, the capacity to wait for food reward represents an operational measure of impulsive behaviour in animals. Food deprived male rats (body weight reduced by approximately 20%) were trained in a T-maze to choose between a small and immediate reward and a larger but delayed reward (Bizot et al., 1999). In the first experiment, SHR, WKY and Wistar adult rats (8- to 13-weeks old; weight range, SHR: 206-253g, WKY: 220-310g, Wistar: 225-292g) were trained to choose between one arm of the T-maze giving immediate access to two food pellets and the other arm giving access to ten pellets after a 15s waiting period. The percentage of choice of the large but delayed reward was slightly and significantly lower (F(2, 42) = 4.17, p<0.05) in SHR (mean ± sem: 65 ± 3%; n=18) than in WKY (75 ± 3%; n=18) and Wistar (77 ± 3%; n=9). The delay before access to the large reward was then lengthened to 30 s and the percentage of choice of the large but delayed reward progressively decreased to about 20% (SHR: 17 ± 4, WKY: 23 ± 3, Wistar: 17 ± 7). There was no longer any between-strain difference and methylphenidate (3 mg/kg) failed to modify choice in the three strains. In the second experiment, juvenile Wistar rats ( 4.5- to 6.5-week old at the time of drug testing; weight range: 76-184g) were trained in the T-maze to choose between one immediate food pellet and five pellets delayed by 30 s. By the end of the training period, animals selected the arm leading to the large reward on 21 ± 2% of the trials. Methylphenidate increased the percentage of choice of the large but delayed reward significantly at 3 mg/kg (+28 ± 5%, t(8)= 6.08, p<0.001) and 5 mg/kg (+38 ± 11%, t(8)= 3.46, p<0.01) but not at 1 mg/kg (+5 ± 3%; t(7)= 1.53, ns) and 10 mg/kg (+10 ± 7%; t(7)= 1.34, ns).

These data support the idea that adult SHR are more impulsive than rats of the two other strains. However, methylphenidate failed to attenuate impulsive-like behaviour in adult SHR as well as in control strains casting doubt on the validity of the SHR as a model of ADHD. On the other hand, the reduction of impulsive-like behaviour by methylphenidate in juvenile Wistar rats indicates that the use of juvenile animals in the T-maze procedure may be suitable for evaluating the therapeutic potential of drugs intended for the treatment of ADHD in children.

Bizot, J et al., (1999) Psychopharmacology146: 400-12.
Rapoport, JL et al., (2002) J Attend Disord 6: Suppl 1, S57-60