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A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation

BACKGROUND: Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effec...

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Autores principales: Tozzi, Alessandro, de Iure, Antonio, Marsili, Valentina, Romano, Rosaria, Tantucci, Michela, Di Filippo, Massimiliano, Costa, Cinzia, Napolitano, Francesco, Mercuri, Nicola Biagio, Borsini, Franco, Giampà, Carmen, Fusco, Francesca Romana, Picconi, Barbara, Usiello, Alessandro, Calabresi, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371006/
https://www.ncbi.nlm.nih.gov/pubmed/22715379
http://dx.doi.org/10.1371/journal.pone.0038312
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author Tozzi, Alessandro
de Iure, Antonio
Marsili, Valentina
Romano, Rosaria
Tantucci, Michela
Di Filippo, Massimiliano
Costa, Cinzia
Napolitano, Francesco
Mercuri, Nicola Biagio
Borsini, Franco
Giampà, Carmen
Fusco, Francesca Romana
Picconi, Barbara
Usiello, Alessandro
Calabresi, Paolo
author_facet Tozzi, Alessandro
de Iure, Antonio
Marsili, Valentina
Romano, Rosaria
Tantucci, Michela
Di Filippo, Massimiliano
Costa, Cinzia
Napolitano, Francesco
Mercuri, Nicola Biagio
Borsini, Franco
Giampà, Carmen
Fusco, Francesca Romana
Picconi, Barbara
Usiello, Alessandro
Calabresi, Paolo
author_sort Tozzi, Alessandro
collection PubMed
description BACKGROUND: Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. PRINCIPAL FINDINGS: Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. CONCLUSIONS: The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine.
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spelling pubmed-33710062012-06-19 A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation Tozzi, Alessandro de Iure, Antonio Marsili, Valentina Romano, Rosaria Tantucci, Michela Di Filippo, Massimiliano Costa, Cinzia Napolitano, Francesco Mercuri, Nicola Biagio Borsini, Franco Giampà, Carmen Fusco, Francesca Romana Picconi, Barbara Usiello, Alessandro Calabresi, Paolo PLoS One Research Article BACKGROUND: Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. PRINCIPAL FINDINGS: Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. CONCLUSIONS: The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine. Public Library of Science 2012-06-08 /pmc/articles/PMC3371006/ /pubmed/22715379 http://dx.doi.org/10.1371/journal.pone.0038312 Text en Tozzi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tozzi, Alessandro
de Iure, Antonio
Marsili, Valentina
Romano, Rosaria
Tantucci, Michela
Di Filippo, Massimiliano
Costa, Cinzia
Napolitano, Francesco
Mercuri, Nicola Biagio
Borsini, Franco
Giampà, Carmen
Fusco, Francesca Romana
Picconi, Barbara
Usiello, Alessandro
Calabresi, Paolo
A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation
title A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation
title_full A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation
title_fullStr A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation
title_full_unstemmed A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation
title_short A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation
title_sort a2a adenosine receptor antagonism enhances synaptic and motor effects of cocaine via cb1 cannabinoid receptor activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371006/
https://www.ncbi.nlm.nih.gov/pubmed/22715379
http://dx.doi.org/10.1371/journal.pone.0038312
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