Buchborn Tobias, Lyons Taylor, Song Chenchen, Feilding Amanda, Knöpfel Thomas
Laboratory for Neuronal Circuit Dynamics, Department of Medicine, Imperial College, London, UK.
Centre for Psychedelic Research, Department of Medicine, Imperial College, London, UK.
J Psychopharmacol. 2020 Jul;34(7):786-794. doi: 10.1177/0269881120903465. Epub 2020 Feb 12.
Serotonin 2A receptors, the molecular target of psychedelics, are expressed by neuronal and vascular cells, both of which might contribute to brain haemodynamic characteristics for the psychedelic state.
Aiming for a systemic understanding of psychedelic vasoactivity, here we investigated the effect of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine - a new-generation agonist with superior serotonin 2A receptor selectivity - on brain-supplying neck-arterial blood flow.
We recorded core body temperature and employed non-invasive, collar-sensor based pulse oximetry in anesthetised mice to extract parameters of local blood perfusion, oxygen saturation, heart and respiration rate. Hypothesising an overlap between serotonergic pulse- and thermoregulation, recordings were done under physiological and elevated pad temperatures.
N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (1.5 mg/kg, subcutaneous) significantly increased the frequency of heart beats accompanied by a slight elevation of neck-arterial blood flow. Increasing the animal-supporting heat-pad temperature from 37°C to 41°C enhanced the drug's effect on blood flow while counteracting tachycardia. Additionally, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine promoted bradypnea, which, like tachycardia, quickly reversed at the elevated pad temperature. The interrelatedness of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine's respiro-cardiovascular effects and thermoregulation was further corroborated by the drug selectively increasing the core body temperature at the elevated pad temperature. Arterial oxygen saturation was not affected by N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine at either temperature.
Our findings imply that selective serotonin 2A receptor activation modulates systemic cardiovascular functioning in orchestration with thermoregulation and with immediate relevance to brain-imminent neck (most likely carotid) arteries. As carotid branching is a critical last hub to channel cardiovascular output to or away from the brain, our results might have implications for the brain haemodynamics associated with psychedelia.
血清素2A受体是迷幻药的分子靶点，由神经元细胞和血管细胞表达，这两者都可能对迷幻状态下的脑血流动力学特征产生影响。
为了全面了解迷幻药的血管活性，我们研究了N-（2-羟基苄基）-2,5-二甲氧基-4-氰基苯乙胺（一种具有卓越血清素2A受体选择性的新一代激动剂）对供应脑部的颈动脉血流的影响。
我们记录了麻醉小鼠的核心体温，并采用基于领口传感器的无创脉搏血氧测定法来提取局部血液灌注、血氧饱和度、心率和呼吸率的参数。鉴于血清素能的脉搏调节和体温调节之间存在重叠，我们在生理垫温和升高的垫温下进行了记录。
N-（2-羟基苄基）-2,5-二甲氧基-4-氰基苯乙胺（1.5毫克/千克，皮下注射）显著增加了心跳频率，并伴有颈动脉血流略有升高。将动物支撑热垫温度从37°C提高到41°C增强了药物对血流的影响，同时抵消了心动过速。此外，N-（2-羟基苄基）-2,5-二甲氧基-4-氰基苯乙胺促进了呼吸过缓，与心动过速一样，在升高的垫温下迅速逆转。N-（2-羟基苄基）-2,5-二甲氧基-4-氰基苯乙胺的呼吸-心血管效应与体温调节的相关性进一步得到证实，即该药物在升高的垫温下选择性地提高了核心体温。在两种温度下，动脉血氧饱和度均不受N-（2-羟基苄基）-2,5-二甲氧基-4-氰基苯乙胺的影响。
我们的研究结果表明，选择性血清素2A受体激活与体温调节协同调节全身心血管功能，且与即将到达脑部的颈部（最可能是颈动脉）动脉直接相关。由于颈动脉分支是将心血管输出引导至脑部或远离脑部的关键最后枢纽，我们的结果可能对与迷幻状态相关的脑血流动力学产生影响。
