PT546. The abolished rewarding effect of methylphenidate in dopamine transporter knockout mice, a model for attention deficit/hyperactivity disorder

Abstract Objectives: Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous neurobiological disorder characterized by inattention, impulsivity and hyperactivity. Although methylphenidate (MPH) has been used as a medication for AD/HD for many years, it is not well known whether exposure to MPH causes drug dependence. Dopamine transporter knockout (DAT-KO) mice are an AD/HD animal model, developed on the postulated role of DA, especially DAT. In the present study, we investigated rewarding effects of MPH by intracranial self-stimulation (ICSS) procedures using DAT-KO mice. Methods: DAT-KO and wild-type (C57BL/6J) mice (20–25 week old) were used. For the ICSS procedures, mice were trained to nose-poke to receive direct stimulations via an electrode placed in the lateral hypothalamus area. After acquisition of the behavior, either response-rate (progressive ratio) or frequency-rate (fixed ratio) procedures were investigated. Results: In response-rate procedures, DAT-KO mice showed an increased response-rate compared with wild-type mice. Treatment of 5 and 10 mg/kg MPH increased the response-rate in wild-type mice to the same level of that in naive DAT-KO mice. Meanwhile, MPH at the same doses did not affect DAT-KO mouse behaviors. Next, we further investigated effects of high-dose of MPH (60 mg/kg) in frequency-rate procedures. High-dose MPH caused immense decrement in responses at middle to higher frequency ranges (80–160 Hz) in wild-type mice. Further, high-dose MPH also caused decrement in responses at higher frequency ranges (140–160 Hz) in DAT-KO mice. Conclusion: The results suggest that low-dose MPH causes changes in wild-type mice reward system to increase response-rate to the same level as naive DAT-KO mice via DAT inhibition. Meanwhile, high-dose MPH could decrease ICSS behaviors via not only DAT inhibition but also by other mechanisms. Although the role of DAT in AD/HD is still controversial, it might be thought there is less risk of drug dependence to occur in AD/HD patients treated with MPH.