Chiodi Valentina, Ferrante Antonella, Ferraro Luca, Potenza Rosa Luisa, Armida Monica, Beggiato Sarah, Pèzzola Antonella, Bader Michael, Fuxe Kjell, Popoli Patrizia, Domenici Maria Rosaria
Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
J Neurochem. 2016 Mar;136(5):907-17. doi: 10.1111/jnc.13421. Epub 2015 Nov 24.
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.
腺苷A2A受体（A2ARs）和大麻素CB1受体（CB1Rs）在纹状体中高度表达，它们在功能上相互作用并形成A2A/CB1异源受体复合物。我们研究了CB1R激动剂在一种在神经特异性烯醇化酶启动子（NSEA2A大鼠）控制下过表达A2ARs的转基因大鼠品系以及年龄匹配的野生型（WT）动物中的作用。CB1R激动剂WIN 55,212-2（WIN）在NSEA2A大鼠中的作用明显低于WT动物，这通过以下方面得到证明：i）皮质纹状体切片中突触传递的电生理记录；ii）纹状体突触体中谷氨酸流出的测量；iii）关于运动活动的体内实验。此外，虽然WIN的作用在WT动物中受到A2AR激动剂（CGS 21680）和拮抗剂（ZM 241385、KW-6002和SCH-442416）的调节，但A2AR拮抗剂未能影响NSEA2A大鼠中WIN介导的作用。目前的结果表明，在A2AR基因神经元过表达的大鼠中，CB1R激活在纹状体中介导的作用显著降低，这表明A2A和CB1受体的化学计量发生了变化，并为剖析形成或未形成异聚体的A2AR在纹状体功能调节中的参与提供了一种策略。这些发现为纹状体A2ARs和CB1Rs之间存在相互作用提供了更多证据，这种相互作用在纹状体功能调节中起着重要作用。我们在神经元特异性烯醇化酶启动子（NSEA2A）控制下过表达腺苷A2A受体的转基因大鼠中研究了A2A-CB1受体相互作用。在这些大鼠中，我们证明了CB1受体激动剂WIN 55,212-2在调节皮质纹状体突触传递和运动活动方面的作用降低，而CB1受体表达水平相对于WT大鼠没有变化。推测A2A-CB1受体异聚体的表达减少。
