Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor.
Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor.
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DOI：
10.7554/elife.35082
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发表时间：
2018-10-25
期刊：
影响因子：
7.7
通讯作者：
Anticevic A
中科院分区：
文献类型：
--
作者：
Preller KH;Burt JB;Ji JL;Schleifer CH;Adkinson BD;Stämpfli P;Seifritz E;Repovs G;Krystal JH;Murray JD;Vollenweider FX;Anticevic A
麦角酸二乙酰胺（LSD）对多种血清素（5-HT）和多巴胺受体具有激动剂活性。尽管LSD的治疗和科学兴趣，其神经生物学效应的具体受体贡献仍然未知。因此，我们进行了一项双盲、随机、平衡、交叉研究，在此期间，24名健康受试者接受（i）安慰剂+安慰剂，（ii）安慰剂+LSD（100 µg po）或（iii）酮色林（一种选择性5-HT 2A受体拮抗剂）+LSD。我们通过数据驱动的全局脑连接方法量化了静息状态的功能连接，并将其与皮质基因表达图进行了比较。LSD降低了关联性，但同时增加了感觉-躯体运动脑和丘脑的连接。Ketanserin完全阻断了LSD的主观和神经效应。LSD效应的全脑空间模式与人类5-HT 2A受体皮质基因表达相匹配。总之，这些结果强烈暗示LSD的神经药理学中的5-HT 2A受体。因此，这项研究指出了5-HT 2A在LSD机制中的关键作用，这为LSD的神经生物学提供了信息，并指导了基于致幻剂的治疗方法的合理发展。由瑞士国家科学基金会，瑞士神经基质基金会，Usona研究所，NIH，NIAA，NARSAD独立研究者补助金，耶鲁CTSA补助金和斯洛文尼亚研究机构资助。.迷幻药LSD改变思维和感知。使用者可能会产生幻觉，例如，他们会看到不存在的东西。颜色，声音和物体可能会出现扭曲，时间似乎会加快或减慢。这些变化与某些精神疾病（如精神分裂症）中发生的思维和感知变化有一些相似之处。因此，研究LSD如何影响大脑可以深入了解这些条件下的机制。也有证据表明，LSD本身可以帮助减轻抑郁症和焦虑症的症状。Preller等人现在已经使用脑成像来探索LSD对健康志愿者大脑的影响。这表明LSD减少了参与计划和决策的大脑区域之间的交流，但它增加了参与感觉和运动的区域之间的交流。那些大脑中感觉和运动区域之间交流最多的志愿者也报告说LSD对他们的思维和感知的影响最大。Preller等人还发现，另一种名为Ketanserin的药物可以阻止LSD改变不同大脑区域的交流方式。它还防止LSD引起思维和感知的变化。酮色林阻断一种名为血清素2A受体的蛋白质，该蛋白质由一种名为血清素的大脑化学物质激活，该化学物质除其他作用外，有助于调节情绪。通过绘制产生5-羟色胺2A受体的基因的位置，Preller等人表明，该受体存在于LSD摄入后显示出改变的通信的大脑区域，因此精确定位了该受体在LSD效应中的重要性。产生精神病症状的精神障碍影响着全世界大量的人。对LSD如何影响大脑的进一步研究可以帮助我们更好地了解这些症状是如何出现的，也可能导致开发更有效的治疗方法来治疗一系列心理健康问题。
Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown. We therefore conducted a double-blind, randomized, counterbalanced, cross-over studyduring which 24 healthy human participants received either (i) placebo+placebo, (ii) placebo+LSD (100 µg po), or (iii) Ketanserin, a selective 5-HT2A receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps. LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans. Together, these results strongly implicate the 5-HT2A receptor in LSD’s neuropharmacology. This study therefore pinpoints the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics. Funded by the Swiss National Science Foundation, the Swiss Neuromatrix Foundation, the Usona Institute, the NIH, the NIAA, the NARSAD Independent Investigator Grant, the Yale CTSA grant, and the Slovenian Research Agency. . The psychedelic drug LSD alters thinking and perception. Users can experience hallucinations, in which they, for example, see things that are not there. Colors, sounds and objects can appear distorted, and time can seem to speed up or slow down. These changes bear some resemblance to the changes in thinking and perception that occur in certain psychiatric disorders, such as schizophrenia. Studying how LSD affects the brain could thus offer insights into the mechanisms underlying these conditions. There is also evidence that LSD itself could help to reduce the symptoms of depression and anxiety disorders. Preller et al. have now used brain imaging to explore the effects of LSD on the brains of healthy volunteers. This revealed that LSD reduced communication among brain areas involved in planning and decision-making, but it increased communication between areas involved in sensation and movement. Volunteers whose brains showed the most communication between sensory and movement areas also reported the strongest effects of LSD on their thinking and perception. Preller et al. also found that another drug called Ketanserin prevented LSD from altering how different brain regions communicate. It also prevented LSD from inducing changes in thinking and perception. Ketanserin blocks a protein called the serotonin 2A receptor, which is activated by a brain chemical called serotonin that, amongst other roles, helps to regulate mood. By mapping the location of the gene that produces the serotonin 2A receptor, Preller et al. showed that the receptor is present in brain regions that show altered communication after LSD intake, therefore pinpointing the importance of this receptor in the effects of LSD. Psychiatric disorders that produce psychotic symptoms affect vast numbers of people worldwide. Further research into how LSD affects the brain could help us to better understand how such symptoms arise, and may also lead to the development of more effective treatments for a range of mental health conditions.