Actions of methylphenidate on dopaminergic neurons of the ventral midbrain

Background Methylphenidate has been suggested to exert its therapeutic effect mainly by blocking the dopamine transporter. In spite of the importance of this interaction, no detailed information is available yet on its actions on single dopaminergic neurons. Methods We examined the effects of methylphenidate on dopaminergic neurons using electrophysiological recordings from rat midbrain slices. Results Methylphenidate inhibited spontaneous firing and caused a membrane hyperpolarization in current clamp or an outward current in voltage clamp. These effects were antagonized by the D2 receptor antagonist sulpiride. An acute dopamine-depleting treatment of the slices with the dopa-decarboxylase inhibitor carbidopa significantly reduced the effects of methylphenidate. This drug potentiated, in a concentration-dependent manner, cellular responses to exogenous dopamine application. Conclusions Our electrophysiological data are consistent with the hypothesis that methylphenidate inhibits dopamine transporter and suggest that the depression of firing is mediated by the release of newly synthesized dopamine which accumulates extracellularly due to inhibition of its reuptake.