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（ERP）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，如氯胺酮和苯环己哌啶（PCP），已被公认多年。 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，包括经常参加锐舞俱乐部派对的人以及军事和医疗人员。滥用氯胺酮和五氯苯酚的后果包括幻觉、偏执、混乱和认知障碍。虽然许多症状在几小时内消退，但据报道，其他症状持续了许多天。然而，很少有研究涉及影响氯胺酮和五氯苯酚敏感性个体差异的遗传和其他生物因素。 假设：对氯胺酮/五氯苯酚的动物研究表明，其行为影响和细胞毒性取决于遗传背景，表明其作用机制的脆弱性不同。已提出亚麻醉剂量的氯胺酮/PCP主要通过破坏GABA能中间神经元上NMDA受体介导的谷氨酸传递来发挥其作用。这支持了一个假设，即遗传背景可能影响GABA能中间神经元上NMDA介导的传递中断，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开发了一种方法来评估非麻醉小鼠的听觉ERP，初步数据表明氯胺酮在三种近交系小鼠中的差异效应。目的1探讨急性氯胺酮给药对三种近交系小鼠听觉事件相关电位影响的量效关系。目的2将确定慢性氯胺酮对这三种品系听觉ERPs影响的差异敏感性。最后，目标3将确定急性和慢性接触氯胺酮后对长期变化的敏感性。 工作环境：斯坦利精神病学实验治疗中心（英语：Stanley Center for Experimental Therapeutics in Psychiatry）是宾夕法尼亚大学神经精神病学系的一个基础科学实验室，也是宾夕法尼亚大学神经生物学和行为中心的一部分。该实验室拥有进行氯胺酮对小鼠听觉ERP调节的拟议研究所需的所有资源。 未来发展方向：该模型的开发将有助于检查调节氯胺酮和五氯苯酚体内作用的环境、遗传和药理因素。此类研究还将有助于了解神经生物学作用机制、毒性倾向以及旨在预防氯胺酮和五氯苯酚接触后长期后遗症的干预措施的制定等方面的基本知识。

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.