Mechanisms of hallucinogen effects on exploratory behavior in rats and mice

描述（由申请人提供）：该项目的目标是使用啮齿动物模型来阐明滥用致幻药物的行为影响机制，包括LSD和DOI，以及用于娱乐，仪式或宗教背景的天然产品，包括SMeODMT和死藤水茶。基于致幻剂对感觉和情绪刺激反应的深刻影响，行为效应将使用大鼠和小鼠行为模式监测系统提供的探索和调查行为的多变量profile来测量。这些计算机化的系统评估活动、探索和行为组织——啮齿动物在野外行为的三个主要方面。该项目有两个具体目标。第一个目标是描述和确定LSD和死藤水的合成等价物（“Pharmahuasca”）改变大鼠探索行为的具体机制。这些研究将扩展对Pharmahuasca的双相性质的初步调查，类似于lsd的特征，其中探索行为最初被抑制，然后随着时间的推移而增加。我们将测试Pharmahuasca成分之间的代谢相互作用是否有助于lsd样的行为特征，或者是否涉及特定的神经化学或受体相互作用。第二个目的是评估5HT1A和5HT2A 5 -羟色胺受体分别对致幻剂对小鼠探索和调查行为的影响的贡献。我们将对5HTIA和5HT2A受体的选择性拮抗剂和敲除进行研究，以收集证据来检验这两种受体对行为影响的假设。本研究旨在阐明致幻剂急性效应的神经生物学机制，这可能是这些药物滥用的娱乐性使用的原因。这些研究也应该进一步加深我们对血清素能系统行为功能的基本理解。总的来说，这项工作与NIDA的既定使命是一致的，即“利用科学的力量来对付药物滥用和成瘾”。此外，天然产物的精神活性特性研究已被NIDA确定为研究的优先领域。相关性：从公共卫生的角度来看，致幻剂的娱乐性使用是一个值得关注的问题。这项工作将进一步加深我们对这些药物滥用行为影响的基本神经机制的理解。

DESCRIPTION (provided by applicant): The goal of this project is to use rodent models to elucidate the mechanisms underlying the behavioral effects of hallucinogenic drugs of abuse, including LSD and DOI,as well as natural products used in recreational, ritual, or religious contexts, including SMeODMT and Ayahuasca tea. Based on the profound effects of hallucinogens on responses to sensory and emotional stimuli, behavioral effects will be measured using a multivariate profile of exploratory and investigatory behavior provided by rat and mouse Behavioral Pattern Monitor systems. These computerized systems assess activity, exploration, and behavioral organization - three major aspects of rodent behavior in an open field. The project has two specific aims. The first aim is to characterize and identify the specific mechanisms by which LSD and synthetic equivalents of Ayahuasca ("Pharmahuasca") alter exploratory behavior in rats. These studies will extend initial investigations into the nature of the biphasic, LSD-like profile of Pharmahuasca, in which exploratory behavior is initially suppressed and then increases as time progresses. We will test whether metabolic interactions between Pharmahuasca components contribute to the LSD-like behavioral profile, or whether specific neurochemical or receptor interactions are involved. The second aim is to assess the respective contributions of 5HT1A and 5HT2A serotonin receptors to the effects of hallucinogens on exploratory and investigatory behavior in mice. Both selective antagonists and knockouts of 5HTIA and 5HT2A receptors will be studied in order to develop converging evidence to test the hypothesis that both receptors contribute to the behavioral effects. This research is designed to elucidate the neurobiological mechanisms responsible for the acute effects of hallucinogens, which are presumably responsible for the recreational use of these drugs of abuse. These studies should also further our basic understanding of the behavioral functions of serotonergic systems. Collectively, this work is consistent with the stated mission of NIDA to bring "thepower of science to bear on drug abuse and addiction." Additionally, the study of psychoactive properties of natural products has been identified by NIDA as a priority area for research. Relevance: The recreational use of hallucinogens is a concern from a public health standpoint. This work will further our understanding of the basic neural mechanisms mediating the behavioral effects of these drugs of abuse.