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The discriminative stimulus properties of methylphenidate in C57BL/6J mice

McGovern, Robin W.a,d; Middaugh, Lawrence D.a,c; Patrick, Kennerly S.d; Griffin, William C.a,b

doi: 10.1097/FBP.0b013e3283423d92
Original Articles

Methylphenidate (MPH) therapy for attention-deficit/hyperactivity disorder is common in children and adults. Concerns regarding abuse of MPH prompted studies to better understand its pharmacology. We used an established drug discrimination task to determine whether MPH could be discriminated by C57BL/6J (B6) mice. B6 mice learned to discriminate cues produced by racemic MPH (dl-MPH 5.0 mg/kg) or half the dose of pure d-isomer (2.5 mg/kg), and dose–response tests established appropriate reductions in discrimination with declining dose. Importantly, the two drug forms generalized to each other completely in substitution tests; consistent with reports that the l-isomer is pharmacodynamically inactive. An additional experiment indicated that lower doses (1 and 2 mg/kg) of dl-MPH did not support acquisition of MPH discrimination despite extensive training. Mice acquired discrimination of dl-MPH only when the dose was increased to 4 mg/kg. Thus, although these lower doses increased drug lever responding in mice trained on the higher dose, their stimuli were not sufficient to support acquisition of the discrimination task. These findings correspond to earlier studies conducted in our laboratory on threshold doses needed to produce stimulatory effects of motor activity inB6 mice. These preclinical findings provide insight intothe relative potency, and by extension, efficacy of dl-MPH versus d-MPH doses.

aCenter for Drug and Alcohol Programs

Departments of bPsychiatry and Behavioral Science


dPharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA

Correspondence to William C. Griffin III, PhD, Center for Drug and Alcohol Programs, MSC 861, Medical University of South Carolina, Charleston, SC 29425-0742, USA e-mail:

Received April 28, 2010

Accepted October 6, 2010

© 2011 Lippincott Williams & Wilkins, Inc.