Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes
Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes
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DOI：
10.1016/j.bbrc.2013.11.104
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发表时间：
2014-01-03
影响因子：
3.1
通讯作者：
Fuxe, Kjell
中科院分区：
文献类型：
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作者：
Borroto-Escuela, Dasiel O.;Romero-Fernandez, Wilber;Fuxe, Kjell
多巴胺D2(L) r- 5-羟色胺5-HT2AR异构体在HEK293细胞中被证实具有双向受体-受体相互作用。在目前的研究中，D2(L)-5-HT2A异受体复合物的存在也在腹侧纹状体和背侧纹状体的离散区域得到了原位接近结扎试验（PLA）的证实。致幻剂5-HT2AR激动剂LSD和DOI在H-3-raclopride/DA竞争实验中显著增加了d2样拮抗剂H-3-raclopride结合位点的密度，显著降低了高亲和力D2R激动剂结合位点的pK（iH）值，而不是标准5-HT2AR激动剂TCB2和5-HT。在HEK293细胞和腹侧纹状体中也得到了类似的结果。致幻剂5-HT2AR激动剂对D2R密度和亲和力的影响被5-HT2A拮抗剂酮色林阻断。在福斯克林诱导的cre -荧光素酶报告基因试验中，使用共转染而不是D2R单转染的HEK293细胞，DOI和LSD（而不是TCB2）显著增强了D2(L)R激动剂喹匹罗诱导的cre -荧光素酶活性抑制。氟哌啶醇阻断了喹匹罗单用和DO的增强作用。而酮色林仅阻断了DOI和LSD的增强作用。观察到的D2R原聚体识别和信号传导变构增强的机制可能是由致幻剂5-HT2AR激动剂在5-HT2AR原聚体正构位点的偏向性激动剂作用介导的。这一机制可能有助于LSD和DOI的精神病作用，因此D2-5-HT2A异受体复合物可能是致幻5-HT2A激动剂精神病作用的靶点。(C) 2013爱思唯尔公司版权所有。
Dopamine D2(L)R-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2(L)-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist H-3-raclopride binding sites and significantly reduced the pK(iH) values of the high affinity D2R agonist binding sites in H-3-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2(L)R agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DO! and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists. (C) 2013 Elsevier Inc. All rights reserved.