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 D(2) 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.
Federici
Mauro
M
Laboratory of Experimental Neurology, IRCCS-Fondazione Santa Lucia, Rome, Italy.
Geracitano
Raffaella
R
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
D000200:Action Potentials / Q000187:drug effects / Q000528:radiation effects; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002230:Carbidopa / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects; D008774:Methylphenidate / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012110:Reserpine / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D008774:Methylphenidate; D013469:Sulpiride; D012110:Reserpine; D003042:Cocaine; D002230:Carbidopa; D004298:Dopamine