Halberstadt Adam L
Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States.
Pharmacol Biochem Behav. 2016 Apr;143:1-10. doi: 10.1016/j.pbb.2016.01.005. Epub 2016 Jan 15.
Monoamine oxidase inhibitors (MAOIs) are often ingested together with tryptamine hallucinogens, but relatively little is known about the consequences of their combined use. We have shown previously that monoamine oxidase-A (MAO-A) inhibitors alter the locomotor profile of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in rats, and enhance its interaction with 5-HT2A receptors. The goal of the present studies was to investigate the mechanism for the interaction between 5-MeO-DMT and MAOIs, and to determine whether other behavioral responses to 5-MeO-DMT are similarly affected. Hallucinogens disrupt prepulse inhibition (PPI) in rats, an effect typically mediated by 5-HT2A activation. 5-MeO-DMT also disrupts PPI but the effect is primarily attributable to 5-HT1A activation. The present studies examined whether an MAOI can alter the respective contributions of 5-HT1A and 5-HT2A receptors to the effects of 5-MeO-DMT on PPI. A series of interaction studies using the 5-HT1A antagonist WAY-100,635 and the 5-HT2A antagonist MDL 11,939 were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in rats pretreated with an MAOI. The effects of MAO-A inhibition on the pharmacokinetics of 5-MeO-DMT and its metabolism to bufotenine were assessed using liquid chromatography-electrospray ionization-selective reaction monitoring-tandem mass spectrometry (LC-ESI-SRM-MS/MS). 5-MeO-DMT (1mg/kg) had no effect on PPI when tested 45-min post-injection but disrupted PPI in animals pretreated with the MAO-A inhibitor clorgyline or the MAO-A/B inhibitor pargyline. The combined effect of 5-MeO-DMT and pargyline on PPI was antagonized by pretreatment with either WAY-100,635 or MDL 11,939. Inhibition of MAO-A increased the level of 5-MeO-DMT in plasma and whole brain, but had no effect on the conversion of 5-MeO-DMT to bufotenine, which was found to be negligible. The present results confirm that 5-MeO-DMT can disrupt PPI by activating 5-HT2A, and indicate that MAOIs alter 5-MeO-DMT pharmacodynamics by increasing its accumulation in the central nervous system.
单胺氧化酶抑制剂（MAOIs）常与色胺类致幻剂一同摄入，但对于它们联合使用的后果人们了解相对较少。我们之前已经表明，单胺氧化酶A（MAO - A）抑制剂会改变大鼠体内致幻剂5 - 甲氧基 - N，N - 二甲基色胺（5 - MeO - DMT）的运动模式，并增强其与5 - HT2A受体的相互作用。本研究的目的是探究5 - MeO - DMT与MAOIs之间相互作用的机制，并确定5 - MeO - DMT的其他行为反应是否也受到类似影响。致幻剂会破坏大鼠的前脉冲抑制（PPI），这一效应通常由5 - HT2A激活介导。5 - MeO - DMT也会破坏PPI，但该效应主要归因于5 - HT1A激活。本研究考察了一种MAOI是否能改变5 - HT1A和5 - HT2A受体对5 - MeO - DMT影响PPI的各自贡献。使用5 - HT1A拮抗剂WAY - 100,635和5 - HT2A拮抗剂MDL 11,939进行了一系列相互作用研究，以评估这些受体对用MAOI预处理的大鼠中5 - MeO - DMT行为效应的各自贡献。使用液相色谱 - 电喷雾电离 - 选择性反应监测 - 串联质谱法（LC - ESI - SRM - MS/MS）评估MAO - A抑制对5 - MeO - DMT药代动力学及其代谢为蟾蜍色胺的影响。注射后45分钟测试时，5 - MeO - DMT（1mg/kg）对PPI没有影响，但在用MAO - A抑制剂氯吉兰或MAO - A/B抑制剂帕吉林预处理的动物中会破坏PPI。5 - MeO - DMT和帕吉林对PPI的联合作用可被WAY - 100,635或MDL 11,939预处理所拮抗。MAO - A的抑制增加了血浆和全脑中5 - MeO - DMT的水平，但对5 - MeO - DMT转化为蟾蜍色胺没有影响，发现该转化可忽略不计。目前的结果证实5 - MeO - DMT可通过激活5 - HT2A破坏PPI，并表明MAOIs通过增加其在中枢神经系统中的蓄积来改变5 - MeO - DMT的药效学。
