title: Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors.
abstract: Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2 A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2 A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2 A Rs, the effects mediated by CB1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A2A and CB1 receptors and providing a strategy to dissect the involvement of A2 A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2 A Rs and CB1 Rs, playing a fundamental role in the regulation of striatal functions. We studied A2A -CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A ). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A -CB1 receptor heteromers is postulated.
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Chiodi
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ferrante
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Rosa Luisa
authors.initials: RL
authors.lastname: Potenza
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Armida
authors.affiliation: Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Beggiato
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pèzzola
authors.affiliation: Max-Delbrűck-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Popoli
authors.affiliation: Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Domenici
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D002186:Cannabinoids; D043705:Receptor, Adenosine A2A; D043884:Receptor, Cannabinoid, CB1; D000241:Adenosine
keywords: WIN 55212-2; adenosine A2A receptor; cannabinoid CB1 receptor; locomotor activity; striatum; synaptic transmission