Dremencov Eliyahu, Lacinova Lubica, Flik Gunnar, Folgering Joost Ha, Cremers Thomas Ifh, Westerink Ben Hc
Institute of Molecular Physiology and Genetics, Centre for Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia.
Gen Physiol Biophys. 2017 Oct;36(4):431-441. doi: 10.4149/gpb_2017039. Epub 2017 Aug 31.
It was previously reported that adenosine-2A (A2A) receptors interact with dopamine-2 (D2) receptors on a molecular level. The aim of the current study was to investigate the functional output of this interaction. In vivo microdialysis was used to assess the effects of an antagonist of A2A receptors, ZM 241385, and an antagonist of D2 receptors haloperidol, either alone or in combination, on brain catecholamine levels. It was found that ZM 241385 did not alter catecholamine levels by its own, but potentiated haloperidol-induced dopamine and norepinephrine release in the nucleus accumbens and prefrontal cortex, respectively. In vivo electrophysiology was used to assess the effect of an agonist (CGS 216820) and an antagonist (ZM 241385) of A2A receptors on the excitability of dopamine and norepinephrine neurons. It was found that CGS 216820 dose-dependently inhibited dopamine and norepinephrine neurons and ZM 241385 reversed this inhibition. In conclusion, those A2A receptors modulate brain catecholamine transmission, and this modulation is mediated, at least in part, via the regulation of excitability of norepinephrine and dopamine neurons. The ability of antagonists of A2A receptors to potentiate the effect of haloperidol on brain norepinephrine and dopamine levels may enhance its clinical efficacy as an antipsychotic drug.
先前有报道称，腺苷2A（A2A）受体与多巴胺2（D2）受体在分子水平上相互作用。本研究的目的是探讨这种相互作用的功能输出。采用体内微透析技术，评估A2A受体拮抗剂ZM 241385和D2受体拮抗剂氟哌啶醇单独或联合使用对脑内儿茶酚胺水平的影响。结果发现，ZM 241385单独使用时不会改变儿茶酚胺水平，但分别增强了氟哌啶醇诱导的伏隔核和前额叶皮质中多巴胺和去甲肾上腺素的释放。采用体内电生理学方法，评估A2A受体激动剂（CGS 216820）和拮抗剂（ZM 241385）对多巴胺能和去甲肾上腺素能神经元兴奋性的影响。结果发现，CGS 216820剂量依赖性地抑制多巴胺能和去甲肾上腺素能神经元，而ZM 241385可逆转这种抑制作用。总之，A2A受体调节脑内儿茶酚胺传递，且这种调节至少部分是通过调节去甲肾上腺素能和多巴胺能神经元的兴奋性介导的。A2A受体拮抗剂增强氟哌啶醇对脑内去甲肾上腺素和多巴胺水平影响的能力，可能会提高其作为抗精神病药物的临床疗效。
