Takaba Rika, Ibi Daisuke, Yoshida Keisuke, Hosomi Eri, Kawase Ririna, Kitagawa Hiroko, Goto Hirotaka, Achiwa Mizuki, Mizutani Kento, Maede Kyosuke, González-Maeso Javier, Kitagaki Shinji, Hiramatsu Masayuki
Meijo University.
Virginia Commonwealth University School of Medicine.
Res Sq. 2023 Jul 7:rs.3.rs-3138705. doi: 10.21203/rs.3.rs-3138705/v1.
Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT 2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic-and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice 24 h post-treatment. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than an anxiolytic effects.
血清素能致幻剂，如裸盖菇素、麦角酸二乙酰胺和DOI，通过激活血清素5-HT 2A受体（5-HT2A）发挥致幻作用。最近的研究表明，血清素能致幻剂对神经精神疾病具有治疗潜力，包括重度抑郁和焦虑相关疾病。然而，5-HT2A在介导这些药物治疗作用中的作用仍不清楚。在本研究中，我们采用行为药理学方法分析了5-HT2A在小鼠中血清素能致幻剂（如裸盖菇素的活性代谢物脱磷酸裸盖菇素、DOI和TCB-2）产生抗焦虑和抗抑郁样作用中的作用。急性腹腔注射致幻剂的小鼠在强迫游泳试验（FST）和悬尾试验（TST）中的不动时间，在给药后24小时显著短于给予赋形剂的对照小鼠。用5-HT2A拮抗剂沃利色林预处理可消除这些作用。令人惊讶的是，急性脱磷酸裸盖菇素治疗后FST中不动时间的减少持续了至少三周。在新奇抑制摄食试验（NSFT）中，急性给予脱磷酸裸盖菇素可缩短摄食潜伏期，这是一种焦虑样行为指标；然而，用沃利色林预处理并不能减弱这种作用。相比之下，DOI和TCB-2对小鼠的NSFT表现没有影响。此外，脱磷酸裸盖菇素、DOI和TCB-2治疗对自发运动活动或头部抽搐反应（啮齿动物中的一种幻觉样行为）没有影响。这些结果表明，5-HT2A有助于血清素能致幻剂的抗抑郁作用，而非抗焦虑作用。
