Neurobehavioral effects of racemic threo-methylphenidate and its d and l enantiomers in rats

Abstract

d, l-Methylphenidate (Ritalin®) is used to treat attention deficit hyperactivity disorder (ADHD) in children. The therapeutic effect is predominantly due to the d enantiomer. Dexmethylphenidate ( d-MPH; Focalin®) was therefore developed for its better therapeutic index. The present study determined and compared the acute behavioral toxicity of d, l-MPH, d-MPH and l-MPH in rats after oral dosing. Comprehensive functional observational battery (FOB) evaluations and rota-rod tests were performed 30, 60 and 120 min after dosing. Ten rats/sex/dose were administered a single dose of vehicle, 2, 20, 100 mg/kg d, l-MPH and 1, 10, 50 mg/kg d-MPH or 1, 100, 500 mg/kg l-MPH. There was no mortality. Certain FOB evaluations were statistically significant from vehicle control at any of the time points with most occurring at 60 and 120 min in the high d, l-MPH dose. These included increases in rearing, difficulty in removal from box, arousal, click, tail-pinch and decreases in hind-limb splay distance, hind-limb grip strength and handling reactivity. Behavioral responses were also present at the mid-dose d, l-MPH and high dose d- and l-MPH. Responses in female were significantly different from males in d, l- and l-MPH groups suggesting a sex difference in sensitivity. In the rota-rod test, mean latency to remain on the rod was significantly less for males compared to control given high dose d-MPH and d, l-MPH. In females, latency times were significantly less for high doses of all three compounds. In summary, fewer significant FOBs were seen with d- and l-MPH compared to equimolar doses of d, l-MPH. l-MPH was the least potent in producing FOBs. These results were supported by rota-rod studies.