Effect of chronic antipsychotic medication administration on cocaine poisoning

长期服用抗精神病药物对可卡因中毒的影响

• 批准号: 7018053
• 负责人: KENNON James HEARD
• 金额: $ 16.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018053
• 关键词: cocaine; neurotransmitter receptor; receptor

DESCRIPTION (provided by applicant): This K08 Career Development Award will provide Assistant Professor Kennon Heard, MD, protected time so he can obtain the basic research training and experience that he requires to become a successful independent investigator focusing on poisoning from drugs of abuse. As an emergency physician and medical toxicologist, Dr. Heard encounters patients suffering from acute abused drug intoxication every day. His long-term objective as an independent investigator is to evaluate novel therapies for such acute poisoning. He will work closely with his sponsor, Dr. Nancy R. Zahniser, an experienced cocaine researcher who has successfully mentored 20 graduate and post-graduate trainees. His proposed career development program includes writing a scholarly review summarizing the mechanisms of cocaine toxicity, taking graduate classes in CMS pharmacology and the responsible conduct of research, and completing a project to help him develop effective mentoring skills. His proposed research project arose from the observation that while almost a quarter of cocaine users have serious mental illness, little is known about the effects of psychiatric medications on the toxic effects of cocaine. A mouse model will be used to study the effect of long-term antipsychotic medication (ARM) administration on the toxic effects of a single high dose of cocaine. Cocaine blocks all three monoamine transporters, and chronic ARM administration increases the density of several neurotransmitter receptors. Dr. Heard hypothesizes that long-term administration of particular APMs will differentially alter the regional density of receptors that mediate cocaine toxicity and that these changes will differentially alter the dose-response for cocaine toxicity. Aim 1 will measure regional receptor and monoamine transporter density in mice treated for 28 days with continuous infusions of clinically relevant APMs (haloperidol, clozapine, ziprasidone, and aripiprazole) or placebo. In vitro radioligand binding and autoradiography will be used to measure the regional density of D1 and D2 dopamine; 5-HT1A, 5-HT2A, 5-HT2C and 5-HT3 serotonin; a1- and a2-adrenergic; NMDA and AMPA glutamate; GABAA; muscarinic cholinergic; and sigma receptors and of monoamine transporters. Aim 2 will determine the effect of the 28-day APM infusion on the cocaine dose required to produce seizures and lethality (ED50 and apparent LD50, respectively). Aim 3 will determine whether selective antagonists of the receptors found to be increased in Aim 1 will attenuate any altered sensitivity to cocaine observed in Aim 2. The results will identify which receptors are altered and how the susceptibility to cocaine toxicity is related to these receptor changes. This experiment will model acute cocaine use by patients taking APMs. Identifying the involved receptor systems will facilitate future studies to determine if chronic APM therapy causes the same receptor changes in humans and, therefore, may cause similar altered susceptibility to cocaine poisoning.

描述（由申请人提供）： 该K 08职业发展奖将为助理教授Kennon Heard（医学博士）提供受保护的时间，以便他能够获得所需的基础研究培训和经验，成为一名成功的独立调查员，专注于滥用药物中毒。作为一名急诊医生和医学毒理学家，赫德博士每天都会遇到急性滥用药物中毒的病人。作为一名独立研究者，他的长期目标是评估这种急性中毒的新疗法。他将与他的赞助商南希博士密切合作。Zahniser是一位经验丰富的可卡因研究人员，他成功地指导了20名研究生和研究生学员。他提出的职业发展计划包括撰写一篇学术评论，总结可卡因毒性的机制，参加CMS药理学和负责任的研究行为的研究生课程，并完成一个项目，以帮助他发展有效的指导技能。他提出的研究项目源于这样的观察，即虽然近四分之一的可卡因使用者患有严重的精神疾病，但人们对精神药物对可卡因毒性作用的影响知之甚少。将使用小鼠模型研究长期抗精神病药物（ARM）给药对单次高剂量可卡因毒性作用的影响。可卡因阻断所有三种单胺转运蛋白，长期ARM给药增加了几种神经递质受体的密度。Heard博士假设，长期服用特定的杀伤人员地雷将不同程度地改变介导可卡因毒性的受体的区域密度，这些变化将不同程度地改变可卡因毒性的剂量反应。目的1将测量连续输注临床相关APM（氟哌啶醇、氯氮平、齐拉西酮和阿立哌唑）或安慰剂治疗28天的小鼠的局部受体和单胺转运蛋白密度。将使用体外放射性配体结合和放射自显影术测量D1和D2多巴胺; 5-HT 1A、5-HT 2A、5-HT 2C和5-HT 3血清素; α 1-和α 2-肾上腺素能; NMDA和AMPA谷氨酸盐; GABAA;毒蕈碱胆碱能; σ受体和单胺转运蛋白的区域密度。目的2将确定28天APM输注对产生癫痫发作和致死性所需的可卡因剂量（分别为ED 50和表观LD 50）的影响。目标3将确定在目标1中发现增加的受体的选择性拮抗剂是否将减弱在目标2中观察到的对可卡因的任何改变的敏感性。研究结果将确定哪些受体被改变，以及可卡因毒性的易感性如何与这些受体的变化相关。该实验将模拟服用APM的患者急性可卡因使用。识别相关的受体系统将有助于未来的研究，以确定慢性APM治疗是否会导致人类相同的受体变化，因此可能会导致类似的可卡因中毒易感性改变。