Functional interaction between pre-synaptic α6β2-containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum
Functional interaction between pre-synaptic α6β2-containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum
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DOI：
10.1111/bph.12234
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发表时间：
2013-08-01
影响因子：
7.3
通讯作者：
Koefalvi, A.
中科院分区：
文献类型：
--
作者：
Garcao, P.;Szabo, E. C.;Koefalvi, A.
突触前烟碱ACh受体（nAChR）和腺苷A（2A）受体（A（2A）Rs）参与多巴胺释放的控制，并且是帕金森病和成瘾的假定治疗靶点。由于A（2A）Rs与nAChRs相互作用的研究已被报道，本研究旨在探讨A（2A）Rs与nAChRs在大鼠纹状体多巴胺能神经末梢中可能的功能相互作用。实验方法我们在体外研究了多巴胺的释放，确定了nAChR亚单位在大鼠纹状体神经末梢中的定位，并在大鼠体内进行了运动行为敏化。A（2A）R选择性激动剂CGS 21680抑制烟碱刺激的[H-3]多巴胺（[H-3]DA）释放，而A（2A）R拮抗剂ZM 241385增强烟碱刺激的[H-3]DA释放。阻断含α 6亚基的nAChR后，剩余尼古丁刺激的[H-3]DA释放不再受A（2A）R配体调节。在自发致敏实验中，尼古丁在重复注射尼古丁的第7天增强了自发活动，这种作用在停药1周后不再持续。值得注意的是，ZM 241385注射大鼠的自发敏化尼古丁已经在第2天，这仍然是持久的尼古丁withdrawal.CONCLUSIONS和IMPLICATIONS这些结果提供了第一个证据，烟碱和腺苷A（2A）R在纹状体多巴胺能末梢之间的功能相互作用，与吸烟，帕金森病和其他多巴胺能疾病的可能治疗后果。
BACKGROUND AND PURPOSEPre-synaptic nicotinic ACh receptors (nAChRs) and adenosine A(2A) receptors (A(2A)Rs) are involved in the control of dopamine release and are putative therapeutic targets in Parkinson's disease and addiction. Since A(2A)Rs have been reported to interact with nAChRs, here we aimed at mapping the possible functional interaction between A(2A)Rs and nAChRs in rat striatal dopaminergic terminals.EXPERIMENTAL APPROACHWe pharmacologically characterized the release of dopamine and defined the localization of nAChR subunits in rat striatal nerve terminals in vitro and carried out locomotor behavioural sensitization in rats in vivo.KEY RESULTSIn striatal nerve terminals, the selective A(2A)R agonist CGS21680 inhibited, while the A(2A)R antagonist ZM241385 potentiated the nicotine-stimulated [H-3] dopamine ([H-3]DA) release. Upon blockade of the alpha 6 subunit-containing nAChRs, the remaining nicotine-stimulated [H-3]DA release was no longer modulated by A(2A)R ligands. In the locomotor sensitization experiments, nicotine enhanced the locomotor activity on day 7 of repeated nicotine injection, an effect that no longer persisted after 1 week of drug withdrawal. Notably, ZM241385-injected rats developed locomotor sensitization to nicotine already on day 2, which remained persistent upon nicotine withdrawal.CONCLUSIONS AND IMPLICATIONSThese results provide the first evidence for a functional interaction between nicotinic and adenosine A(2A)R in striatal dopaminergic terminals, with likely therapeutic consequences for smoking, Parkinson's disease and other dopaminergic disorders.