致幻5-HT2A受体（5-HT2AR）激动剂诱导的头部抽搐反应（HTR）受Gs信号通路调节。5-HT2AR和代谢型谷氨酸mGlu2受体（mGluR2）之间异二聚体的形成对于致幻5-HT2AR激动剂诱导的HTR至关重要。为了研究mGluR2激动剂和反向激动剂对致幻5-HT2AR激动剂DOM诱导的HTR的影响，用mGluR2激动剂(LY379268、LY354740、LY404039)或反向激动剂LY341495预处理C57BL/6小鼠,并在立即施用DOM后手动计数HTR。在共表达5-HT2AR和mGluR2的人胚胎肾-293(HEK-293)T型细胞中,进行IP-One(IP1)HTRF测定和cAMP测定以评估LY341495或LY354740对DOM诱导的Gq和Gs活化的影响。结果表明，DOM诱导的小鼠HTR被LY379268，LY354740和LY404039剂量依赖性抑制，而LY341495剂量依赖性增强。此外，LY341495逆转了LY354740对DOM诱导的HTR的抑制作用。在共表达5-HT2AR和mGluR2的HEK-293T细胞中，DOM诱导的cAMP水平被LY354740降低，被LY341495升高，但DOM诱导的IP1水平不受LY354740或LY341495调节。mGluR2激动剂和反向激动剂对DOM诱导的HTR的调控与5-HT2AR介导的Gs信号通路密切相关。在共表达5-HT2AR和mGluR2A677S/A681P/A685G突变体（mGluR23A突变体）的HEK-293T细胞中，DOM诱导的cAMP水平不受LY354740的调节，但LY341495显着增强。5-HT2AR/mGluR2异二聚体对于DOM诱导的HTR和cAMP水平至关重要，两者均被mGluR2激动剂抑制并被mGluR2反向激动剂增强。
Hallucinogenic 5-HT2A receptor (5-HT2AR) agonists-induced head-twitch response (HTR) is regulated by Gs signaling pathway. Formation of heterodimers between 5-HT2AR and metabotropic glutamate mGlu2 receptor (mGluR2) is essential for the hallucinogenic 5-HT2AR agonist-induced HTR. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HT2AR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately. IP-One (IP1) HTRF assay and cAMP assay were performed to evaluate the effect of LY341495 or LY354740 on DOM-induced Gq and Gs activation in Human Embryonic Kidney-293 (HEK-293) T-type cells co-expressing 5-HT2AR and mGluR2. The results showed that DOM-induced HTR in mice was dose-dependently inhibited by LY379268, LY354740, and LY404039, while it was dose-dependently enhanced by LY341495. Moreover, LY341495 reversed the inhibitory effect of LY354740 on DOM-induced HTR. In HEK-293T cells co-expressing 5-HT2AR and mGluR2, DOM-induced cAMP level was decreased by LY354740 and increased by LY341495, but DOM-induced IP1 level was not regulated by LY354740 or LY341495. The regulation of DOM-induced HTR by mGluR2 agonists and inverse agonists is closely related to 5-HT2AR-mediated Gs signaling pathway. In HEK-293T cells co-expressing 5-HT2AR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HT2AR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists.
