Evoked potentials and vulnerability to ketamine in mice.

描述(由申请人提供)： 这项尖端基础研究奖提案中的研究将创建一个小鼠模型，使用听觉事件相关电位(ERPs)来评估NMDA拮抗剂药物滥用的体内生理效应的遗传变异性。 背景：滥用NMDA受体拮抗剂，如氯胺酮和苯环利定(PCP)，多年来已被认识到。然而，最近的研究表明，氯胺酮滥用在一部分人群中变得更加普遍，包括经常参加狂欢俱乐部派对的人，以及军事和医务人员。滥用氯胺酮和五氯苯酚的后果包括幻觉、偏执、组织混乱和认知障碍。虽然许多症状在几个小时内就会消失，但据报道，其他症状会持续很多天。然而，很少有研究涉及遗传和其他生物因素，以及影响氯胺酮和五氯苯酚敏感性的个体差异。 假设：对氯胺酮/五氯苯酚的动物研究表明，它们的行为效应和细胞毒性取决于遗传背景，这表明它们的作用机制存在不同的脆弱性。亚麻醉剂量氯胺酮/五氯苯酚的作用主要是通过阻断NMDA受体介导的GABA能中间神经元上的谷氨酸传递来实现的。这支持了一种假说，即遗传背景可能影响NMDA介导的GABA能中间神经元传递的中断，以调节PCP/氯胺酮滥用的急性表现和长期后遗症。 研究项目：PI已经开发了一种方法来评估非麻醉小鼠的听觉ERPs，初步数据表明氯胺酮在三个近交系小鼠中的作用不同。目的1研究氯胺酮急性给药对三种近交系小鼠听觉事件相关电位的影响及其量效关系。目标2随后将确定这三个菌株对慢性氯胺酮影响听觉事件相关电位的不同敏感性。最后，目标3将确定对急性和慢性暴露于氯胺酮后的长期变化的敏感性。 环境：斯坦利精神病学实验治疗中心是神经精神病学分部的基础科学实验室，是宾夕法尼亚大学神经生物学和行为中心的一部分。这个实验室拥有进行氯胺酮对小鼠听觉事件相关电位调节的拟议研究所需的所有资源。 未来方向：该模型的发展将有助于检查环境、遗传和药理学因素，这些因素调节氯胺酮和五氯苯酚的体内效应。这类研究还将有助于提供有关神经生物学作用机制、毒性易感性以及制定旨在预防氯胺酮和五氯苯酚暴露后长期后遗症的干预措施的基本知识。

DESCRIPTION (provided by applicant): Studies in this Cutting-Edge Basic Research Award proposal would create a mouse model to assess genetic variability for in vivo physiological effects of NMDA antagonist drugs of abuse using auditory event related potentials (ERPs). Background: Abuse of NMDA receptor antagonists, such as ketamine and phencyclidine (PCP), has been recognized for many years. However, recent studies indicate that ketamine abuse has become more common among a subset of the population including people who frequent rave club parties, as well as military and medical personnel. The consequences of ketamine and PCP abuse include hallucinations, paranoia, disorganization and cognitive impairments. While many symptoms resolve within hours, others have been reported to last for many days. However, few studies have addressed genetic and other biological factors and that influence individual differences in ketamine and PCP sensitivity. Hypothesis: Animal studies with ketamine/PCP indicate that their behavioral effects and cellular toxicity are dependent on genetic background, suggesting differential vulnerability to their mechanism of action. Subanesthetic doses of ketamine/PCP have been proposed to exert their effect primarily by disrupting NMDA receptor-mediated glutamate transmission on GABAergic interneurons. This supports a hypothesis that genetic background may influence disruption of NMDA-mediated transmission on GABAergic interneurons to modulate the acute presentation and long-term sequelae of PCP/ketamine abuse. Research Project: The PI has developed a method to assess auditory ERPs in non-anesthetized mice with preliminary data demonstrating differential effects of ketamine among three inbred mouse strains. Aim 1 would determine the dose response relationship for the effects of acute ketamine administration on auditory ERPs in three inbred mouse strains. Aim 2 would then determine the differential sensitivity to effects of chronic ketamine on auditory ERPs in these three strains. Lastly, Aim 3 would determine the sensitivity to long-term changes following acute and chronic exposure to ketamine. Environment: The Stanley Center for Experimental Therapeutics in Psychiatry is a basic science laboratory within the Division of Neuropsychiatry and is part of The Center for Neurobiology and Behavior at the University of Pennsylvania. This laboratory contains all of the necessary resources to conduct the proposed studies of ketamine modulation of auditory ERPs in mice. Future Directions: Development of this model would facilitate examination of environmental, genetic and pharmacological factors that modulate the in vivo effects of ketamine and PCP. Such studies would also contribute basic knowledge regarding the neurobiological mechanisms of action, predisposition to toxicity and development of interventions directed at prevention of long-term sequelae following ketamine and PCP exposure.