Received for publication June 2, 2008.
Revised August 6, 2008.
Accepted for publication August 11, 2008.

The effects of methylphenidate on knock-in mice with a methylphenidate resistant dopamine transporter

Abstract

Methylphenidate (Ritalin^TM) is one of the most commonly abused prescription drugs. It is a psychostimulant that inhibits the dopamine and norepinephrine transporters with high affinity. In mice, methylphenidate stimulates locomotor activity, is self-administered, and produces conditioned place preference - typical properties of an addictive drug. We have generated a knock-in mouse line bearing a mutant dopamine transporter that is approximately 80-fold less sensitive to cocaine-inhibition than wild type. Interestingly, this mutant is also almost 50-fold less sensitive to methylphenidate-inhibition, suggesting similarities in the binding site for cocaine and methylphenidate. Since methylphenidate is not effective at inhibiting the mutant dopamine transporter, we hypothesized that it would not stimulate locomotor activity or produce reward in the knock-in mice. In these knock-in mice, doses up to 40 mg/kg methylphenidate either inhibit or fail to stimulate locomotor activity, and do not produce conditioned place preference. Doses up to 40 mg/kg methylphenidate also fail to produce stereotypy in the knock-in mice. Nisoxetine and desipramine, selective norepinephrine transporter inhibitors, also reduce locomotor activity in wild type and knock-in mice. These results indicate that enhanced dopaminergic neurotransmission is required for methylphenidate's stimulating and rewarding effects. In addition, we observed that drugs enhancing noradrenergic neurotransmission inhibit locomotor activity in mice, which is consistent with the notion that methylphenidate's ability to inhibit the norepinephrine transporter may contribute to its efficacy in treating attention deficit hyperactivity disorder.

Key words: ADHA, addiction, dopamine transporter, knock-in, methylphenidate, psychostimulant