PT  - JOURNAL ARTICLE
AU  - Tilley, Michael R.
AU  - Gu, Howard H.
TI  - The Effects of Methylphenidate on Knockin Mice with a Methylphenidate-Resistant Dopamine Transporter
AID  - 10.1124/jpet.108.141713
DP  - 2008 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 554--560
VI  - 327
IP  - 2
4099  - http://jpet.aspetjournals.org/content/327/2/554.short
4100  - http://jpet.aspetjournals.org/content/327/2/554.full
SO  - J Pharmacol Exp Ther2008 Nov 01; 327
AB  - Methylphenidate (Ritalin) 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 knockin mouse line bearing a mutant dopamine transporter that is approximately 80-fold less sensitive to cocaine inhibition than wild type. It is interesting to note that this mutant is also almost 50-fold less sensitive to methylphenidate inhibition, suggesting similarities in the binding site for cocaine and methylphenidate. Because methylphenidate is not effective at inhibiting the mutant dopamine transporter, we hypothesized that it would not stimulate locomotor activity or produce reward in the knockin mice. In these knockin 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 knockin mice. Nisoxetine and desipramine, selective norepinephrine transporter inhibitors, also reduce locomotor activity in wild-type and knockin 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. The American Society for Pharmacology and Experimental Therapeutics