Ferreira S G, Gonçalves F Q, Marques J M, Tomé Â R, Rodrigues R J, Nunes-Correia I, Ledent C, Harkany T, Venance L, Cunha R A, Köfalvi A
Neuromodulation Group, CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Laboratory of Neuromodulation and Metabolism, CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Doctoral Programme in Experimental Biology and Biomedicine, CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal.
Br J Pharmacol. 2015 Feb;172(4):1074-86. doi: 10.1111/bph.12970. Epub 2015 Jan 12.
Both cannabinoid CB1 and adenosine A2A receptors (CB1 receptors and A2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB1 -A2A receptor interaction has already been elucidated, but the presynaptic A2A receptor-mediated control of presynaptic neuromodulation by CB1 receptors remains to be defined. Because the corticostriatal terminals provide the major input to the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions.
Pharmacological manipulation of CB1 and A2A receptors was carried out in brain nerve terminals isolated from rats and mice, using flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement. Whole-cell patch-clamp recordings were made in horizontal corticostriatal slices.
Flow synaptometry showed that A2A receptors were extensively co-localized with CB1 receptor-immunopositive corticostriatal terminals and A2A receptors co-immunoprecipitated CB1 receptors in these purified terminals. A2A receptor activation decreased CB1 receptor radioligand binding and decreased the CB1 receptor-mediated inhibition of high-K(+) -evoked glutamate release in corticostriatal terminals. Accordingly, A2A receptor activation prevented CB1 receptor-mediated paired-pulse facilitation and attenuated the CB1 receptor-mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices.
Activation of presynaptic A2A receptors dampened CB1 receptor-mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB1 receptor-mediated presynaptic inhibition, allowing frequency-dependent enhancement of synaptic efficacy at corticostriatal synapses.
大麻素CB1受体和腺苷A2A受体（CB1受体和A2A受体）均控制皮质纹状体突触处的突触传递，对神经和精神疾病具有重要的治疗意义。突触后CB1 - A2A受体相互作用已得到阐明，但CB1受体通过突触前A2A受体介导的对突触前神经调节的控制仍有待明确。由于皮质纹状体终末为基底神经节提供主要输入，了解汇聚于其上的神经调节的相互作用性质将为我们提供新颖且强大的工具，以理解皮质纹状体突触传递的生理学，并解释与病理状况相关的变化。
利用流动突触测定法、免疫沉淀、放射性配体结合、ATP和谷氨酸释放测量，对从大鼠和小鼠分离出的脑神经终末进行CB1和A2A受体的药理学操作。在水平皮质纹状体切片上进行全细胞膜片钳记录。
流动突触测定法显示，A2A受体与CB1受体免疫阳性的皮质纹状体终末广泛共定位，且在这些纯化的终末中，A2A受体与CB1受体共免疫沉淀。A2A受体激活降低了CB1受体放射性配体结合，并降低了CB1受体介导的对皮质纹状体终末中高钾诱发的谷氨酸释放的抑制作用。相应地，A2A受体激活阻止了CB1受体介导的双脉冲易化，并减弱了CB1受体介导的对皮质纹状体切片中谷氨酸能突触处突触传递的抑制作用。
突触前A2A受体的激活减弱了CB1受体介导的对皮质纹状体终末的抑制作用。这构成了一种迄今未被认识的机制，用于调节强大的CB1受体介导的突触前抑制，从而使皮质纹状体突触处的突触效能能够依赖频率增强。
