Behavioral and pharmacokinetic interactions between monoamine oxidase inhibitors and the hallucinogen 5-methoxy-N,N-dimethyltryptamine.
Behavioral and pharmacokinetic interactions between monoamine oxidase inhibitors and the hallucinogen 5-methoxy-N,N-dimethyltryptamine.
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DOI：
10.1016/j.pbb.2016.01.005
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Halberstadt AL
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文献类型：
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作者：
Halberstadt AL
单胺氧化酶抑制剂（MAOIs）经常与色胺致幻剂一起摄入，但对它们联合使用的后果知之甚少。我们以前已经表明，单胺氧化酶-A（MAO-A）抑制剂改变了大鼠的致幻剂5-甲氧基-N，N-二甲基色胺（5-MeO-DMT）的运动概况，并增强其与5-HT 2A受体的相互作用。本研究的目的是调查5-MeO-DMT和MAOI之间的相互作用的机制，并确定是否其他行为反应5-MeO-DMT类似的影响。致幻剂破坏大鼠的前脉冲抑制（PPI），这种作用通常由5-HT 2A激活介导。5-MeO-DMT也破坏PPI，但其作用主要归因于5-HT 1A激活。本研究检查了MAOI是否可以改变5-HT 1A和5-HT 2A受体对5-MeO-DMT对PPI作用的各自贡献。使用5-HT 1A拮抗剂WAY-100635和5-HT 2A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的行为效应的各自贡献。采用液相色谱-电喷雾离子化-选择反应监测-串联质谱（LC-ESI-SRM-MS/MS）技术，研究了单胺氧化酶A抑制剂对5-甲氧基DMT药代动力学及其代谢产物蟾毒替宁的影响。注射后45分钟测试时，5-MeO-DMT（1 mg/kg）对PPI没有影响，但在用MAO-A抑制剂氯吉林或MAO-A/B抑制剂帕吉林预处理的动物中破坏PPI。用WAY-100635或MDL 11，939预处理可拮抗5-MeO-DMT和帕吉林对PPI的联合作用。MAO-A的抑制增加血浆和全脑中5-MeO-DMT的水平，但对5-MeO-DMT转化为蟾毒替宁没有影响，这被发现是可以忽略的。目前的结果证实，5-MeO-DMT可以通过激活5-HT 2A破坏PPI，并表明MAOI通过增加其在中枢神经系统中的积累来改变5-MeO-DMT的药效学。
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-100635 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 (1 mg/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-100635 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.