Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors

Adenosine A2A receptors (A2ARs) and cannabinoid CB1 receptors (CB1Rs) are highly expressed in the striatum, where they functionally interact and form A2A/CB1 heteroreceptor complexes. We investigated the effects of CB1R stimulation in a transgenic rat strain over-expressing A2ARs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1R 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 A2AR agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2AR antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2ARs, 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 A2AR forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2ARs and CB1Rs, playing a fundamental role in the regulation of striatal functions.