Striatal adenosine-cannabinoid receptor interactions in rats overexpressing adenosine A2A receptors.

Adenosine A2A receptors (A2A 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 overexpressing A2A 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 glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal overexpression of A2A Rs the effects mediated by CB1R 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 A2A R forming or not forming heteromers in the modulation of striatal functions. This findings add additional evidence for the existence of an interaction between striatal A2A Rs and CB1Rs, playing a fundamental role in the regulation of striatal functions. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.