Department of Physiology & Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States; Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States.
Department of Physiology & Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States; Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States.
Neurosci Lett. 2022 Sep 25;788:136836. doi: 10.1016/j.neulet.2022.136836. Epub 2022 Aug 10.
Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT receptor (5-HTR). This class of psychoactive substances, which includes lysergic acid diethylamide (LSD), psilocybin, mescaline and the substituted amphetamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), is receiving renewed attention for their potential therapeutic properties as it relates to psychiatric conditions such as depression and substance use disorders. Current studies focused on the potentially clinical effects of psychedelics on human subjects tend to exclude sex as a biological variable. Much of the understanding of psychedelic pharmacology is derived from rodent models, but most of this preclinical research has only focused on male mice. Here we tested the effects of DOI on head-twitch behavior (HTR) - a mouse behavioral proxy of human psychedelic potential - in male and female mice. DOI elicited more HTR in female as compared to male C57BL/6J mice, a sex-specific exacerbated behavior that was not observed in 129S6/SvEv animals. Volinanserin (or M100907) - a 5-HTR antagonist - fully prevented DOI-induced HTR in male and female C57BL/6J mice. Accumulation of inositol monophosphate (IP) in the frontal cortex upon DOI administration showed no sex-related effect in C57BL/6J mice. However, the pharmacokinetic properties of DOI differed among sexes - brain and plasma concentrations of DOI were lower 30 and 60 min after drug administration in female as compared to male C57BL/6J mice. Together, these results suggest strain-dependent and sex-related differences in the behavioral and pharmacokinetic profiles of the 5-HTR agonist DOI in C57BL/6J mice, and support the importance of studying sex as a biological variable in preclinical psychedelic research.
致幻剂，也被称为经典致幻剂，主要通过血清素 5-HT 受体（5-HTR）影响感知、认知和感官处理过程。这一类精神活性物质包括麦角酸二乙酰胺（LSD）、裸盖菇素、三甲氧苯乙胺和取代苯丙胺 1-(2,5-二甲氧基-4-碘苯基)-2-氨基丙烷（DOI），由于其在治疗抑郁症和物质使用障碍等精神疾病方面的潜在治疗特性而受到重新关注。目前，针对致幻剂对人类受试者潜在临床效果的研究往往将性别排除在生物学变量之外。对致幻药理学的大部分了解都源自于啮齿动物模型，但大多数这些临床前研究仅关注雄性小鼠。在这里，我们测试了 DOI 在摇头行为（HTR）中的作用——这是一种人类致幻潜力的小鼠行为替代指标——在雄性和雌性 C57BL/6J 小鼠中的作用。DOI 在雌性 C57BL/6J 小鼠中引起的 HTR 比雄性小鼠更多，这种性别特异性的加剧行为在 129S6/SvEv 动物中没有观察到。Volinanserin（或 M100907）——一种 5-HTR 拮抗剂——完全阻止了 DOI 在雄性和雌性 C57BL/6J 小鼠中引起的 HTR。DOI 给药后，在额皮质中肌醇单磷酸（IP）的积累在 C57BL/6J 小鼠中没有表现出性别相关的影响。然而，DOI 在性别之间的药代动力学特性存在差异——在药物给予后 30 和 60 分钟，雌性 C57BL/6J 小鼠的 DOI 脑和血浆浓度较低。综上所述，这些结果表明在 C57BL/6J 小鼠中，5-HTR 激动剂 DOI 的行为和药代动力学特征存在与品系相关和性别相关的差异，并支持在临床前致幻研究中研究性别作为生物学变量的重要性。
