title: Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP.
abstract: The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Chiodi
authors.affiliation: Department Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Mallozzi
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ferrante
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Jiang F
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Child Study Center, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: Department Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Anna Maria Michela
authors.initials: AM
authors.lastname: Di Stasi
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Popoli
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Domenici
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D043705:Receptor, Adenosine A2A; D014638:Vanadates; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse; D003042:Cocaine