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

Abstract
Adenosine A2A receptors (A2ARs) and cannabinoid CB1 receptors (CB1Rs) are highly expressed in the striatum, where they interact and form A2A/CB1 heteroreceptor complexes. In this study, we explored the effects of CB1R stimulation in a transgenic rat strain, NSEA2A rats, which overexpress A2ARs under the control of the neural-specific enolase promoter, and compared them with age-matched wild-type (WT) rats. We found that the effects of the CB1R agonist WIN 55,212-2 (WIN) were significantly reduced in NSEA2A rats compared to WT animals, as shown by i) electrophysiological recordings of synaptic transmission in corticostriatal slices, ii) glutamate outflow measurements from striatal synaptosomes, and iii) in vivo locomotor activity experiments. In WT rats, the effects of WIN were modulated by both A2AR agonists (CGS 21680) and antagonists (ZM 241385, KW-6002, and SCH-442416), but these A2AR antagonists had no impact on WIN-induced effects in NSEA2A rats. These findings suggest that genetic overexpression of A2ARs in neurons leads to a significant reduction in the effects of CB1R activation in the striatum, likely due to altered stoichiometry between A2A and CB1 receptors. This work provides a strategy to investigate whether A2A receptors form heteromers and their role in modulating striatal functions. Overall, our results offer additional evidence for the functional interaction between striatal A2ARs and CB1Rs, which is crucial for regulating striatal activity. We also observed a reduced impact of CB1 receptor agonist WIN 55,212-2 on corticostriatal synaptic transmission and locomotor activity in NSEA2A rats, despite unchanged CB1 receptor expression levels compared to WT rats, suggesting a reduction in A2A-CB1 receptor heteromer expression.