title: Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate.
abstract: We combined in vitro amperometric, optical analysis of fluorescent false neurotransmitters and microdialysis techniques to unveil that cocaine and methylphenidate induced a marked depression of the synaptic release of dopamine (DA) in mouse striatum. In contrast to the classical dopamine transporter (DAT)-dependent enhancement of the dopaminergic signal observed at concentrations of cocaine lower than 3 μM, the inhibitory effect of cocaine was found at concentrations higher than 3 μM. The paradoxical inhibitory effect of cocaine and methylphenidate was associated with a decrease in synapsin phosphorylation. Interestingly, a cocaine-induced depression of DA release was only present in cocaine-insensitive animals (DAT-CI). Similar effects of cocaine were produced by methylphenidate in both wild-type and DAT-CI mice. On the other hand, nomifensine only enhanced the dopaminergic signal either in wild-type or in DAT-CI mice. Overall, these results indicate that cocaine and methylphenidate can increase or decrease DA neurotransmission by blocking reuptake and reducing the exocytotic release, respectively. The biphasic reshaping of DA neurotransmission could contribute to different behavioral effects of psychostimulants, including the calming ones, in attention deficit hyperactivity disorder.
authors.affiliation: From the Laboratorio di Neurologia Sperimentale, Istituto Ricovero e Cura a carattere scientifico (IRCCS) Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Federici
authors.forename: Emanuele Claudio
authors.initials: EC
authors.lastname: Latagliata
authors.forename: Ada
authors.initials: A
authors.lastname: Ledonne
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Rizzo
authors.forename: Marco
authors.initials: M
authors.lastname: Feligioni
authors.forename: Dave
authors.initials: D
authors.lastname: Sulzer
authors.forename: Matthew
authors.initials: M
authors.lastname: Dunn
authors.forename: Dalibor
authors.initials: D
authors.lastname: Sames
authors.forename: Howard
authors.initials: H
authors.lastname: Gu
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects / Q000235:genetics; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D016704:Synapsins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D018765:Dopamine Uptake Inhibitors; D016704:Synapsins; D008774:Methylphenidate; D003042:Cocaine; D004298:Dopamine
keywords: Amperometry; Cocaine; Dopamine; Dopamine Transporters; Drug Action; Electrophysiology; Microdialysis; Striatum; Transgenic Mice