Mechanisms of hallucinogen effects on exploratory behavior in rats and mice

描述(申请人提供)：这个项目的目标是使用啮齿动物模型来阐明致幻药物滥用的行为影响的机制，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Ayahuasca茶。基于迷幻剂对感觉和情感刺激反应的深刻影响，将使用由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轮廓来测量行为影响。这些计算机化的系统评估活动、探索和行为组织--这是开阔地带啮齿动物行为的三个主要方面。该项目有两个具体目标。第一个目标是确定LSD和Ayahuasca(“Pharmahuasca”)的合成等价物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、LSD样特征的性质的初步调查，在这种情况下，探索行为最初受到抑制，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型5-羟色胺受体在致幻剂对小鼠探索和研究行为的影响中的各自作用。将对5HTIA和5HT2A受体的选择性拮抗剂和敲除进行研究，以发展一致的证据来检验这两种受体对行为效应起作用的假设。这项研究旨在阐明致幻剂的急性影响的神经生物学机制，据推测，迷幻剂是娱乐使用这些滥用药物的原因。这些研究还应该加深我们对5-羟色胺能系统行为功能的基本理解。总体而言，这项工作与NIDA所宣称的使命是一致的，即“利用科学的力量来应对药物滥用和成瘾”。此外，NIDA已将天然产品的精神活性研究确定为优先研究领域。相关性：从公共卫生的角度来看，娱乐使用迷幻剂是一个令人担忧的问题。这项工作将进一步加深我们对这些滥用药物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.