Strain differences in the behavioral responses of male rats to chronically administered methylphenidate

Genetic variability in the behavioral responses of experimental subjects to psychostimulants such as amphetamine and cocaine have been reported. However, genetic differences in the locomotor responses of rat strains to methylphenidate (MPD), a commonly used psychostimulant in the treatment of attention deficit/hyperactivity disorder, have not been extensively investigated. Research using genetically defined rodent strains can enhance our understanding of the role genetic factors play in drug-related behaviors and the development of animal models for drug-sensitive diseases or behaviors. The objective of the present study was to investigate strain differences in the locomotor responses to MPD among three rat strains: Sprague-Dawley (SD), Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR). Eight-week-old adult, male SD, WKY, and SHR were given a regimen of daily MPD administration (0.6, 2.5, or 10 mg/kg, i.p.) for 6 consecutive days followed by 3 days of washout and a day of MPD re-challenge with similar dosages as previously used. An automated activity monitoring system recorded their horizontal activity, total distance traveled, rearing, stereotypic movements, and number of discrete movements. Repeated administration of 0.6 mg/kg MPD produced no significant effect on locomotor activity compared with saline in all three strains. However, there were strain differences in the locomotor activity of SD, SHR, and WKY rats to repeated 2.5- and 10-mg/kg MPD treatment. Repeated administration of 2.5 mg/kg MPD elicited locomotor sensitization in SD and WKY rats but not in SHR. Repeated administration of 10 mg/kg MPD induced locomotor tolerance in SD and WKY rats, while SHR had variable locomotor responses to this MPD dose. In conclusion, rat strains play a significant role in the response to acute and chronic administration of MPD.