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

基本信息

批准号：
7619590
负责人：
KENNON James HEARD
金额：
$ 15.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/7619590
关键词：
A Mouse Accident and Emergency department Acute Adrenergic Agents Affect Affinity Animals Antipsychotic Agents Attenuated Autoradiography Basic Science Binding Brain Brain region Cerebral cortex Cessation of life Chronic Clozapine Cocaine Cocaine Users Continuous Infusion Corpus striatum structure Dopamine Dopamine Receptor Dose Emergency Situation Future GABA Receptor Glutamates HTR2A gene Haloperidol Hearing Hippocampus (Brain)Human In Vitro Infusion procedures Intoxication K-Series Research Career Programs Lethal Dose 50 Long-Term Effects Measures Mediating Medical Mentors Modeling Morbidity - disease rate Mus Muscarinics N-Methylaspartate Neurotransmitter Receptor Neurotransmitters Norepinephrine Nucleus Accumbens Patients Pharmaceutical Preparations Pharmacology Physicians Placebos Poisoning Predisposition Relative (related person)Research Personnel Research Project Grants Research Training Seizures Serotonin Substance abuse problem Synapses System Testing Time Toxic effect Treatment Protocols Work Writing adrenergic aripiprazole attenuation career development cholinergic clinically relevant cocaine use density drug of abuse experience frontal lobe improved monoamine mouse model novel professor programs radioligand receptor receptor density research study response responsible research conduct severe mental illness sigma receptors skills ziprasidone

项目摘要

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）： K08 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，以便他能够获得成为一名成功的独立调查员所需的基础研究培训和经验，专注于滥用药物中毒。作为一名急诊科医生和医学毒理学家，赫德博士每天都会遇到患有急性滥用药物中毒的患者。作为一名独立研究者，他的长期目标是评估治疗此类急性中毒的新疗法。他将与其赞助商 Nancy R. Zahniser 博士密切合作，Nancy R. Zahniser 博士是一位经验丰富的可卡因研究员，已成功指导了 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总结可卡因毒性机制的学术评论、参加 CMS 药理学研究生课程和负责任的研究行为，以及完成一个项目以帮助他培养有效的指导技能。他提出的研究项目源于这样的观察：虽然近四分之一的可卡因使用者患有严重的精神疾病，但人们对精神科药物对可卡因毒性作用的影响知之甚少。小鼠模型将用于研究长期服用抗精神病药物（ARM）对单次高剂量可卡因毒性作用的影响。可卡因会阻断所有三种单胺转运蛋白，而长期服用 ARM 会增加几种神经递质受体的密度。 Heard 博士推测，长期施用特定 APM 将不同程度地改变介导可卡因毒性的受体的区域密度，并且这些变化将不同程度地改变可卡因毒性的剂量反应。目标 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 天的小鼠的区域受体和单胺转运蛋白密度。体外放射性配体结合和放射自显影将用于测量 D1 和 D2 多巴胺的区域密度； 5-HT1A、5-HT2A、5-HT2C 和 5-HT3 血清素； a1-和a2-肾上腺素能； NMDA 和 AMPA 谷氨酸盐；氨基丁酸；毒蕈碱胆碱能;和西格玛受体和单胺转运蛋白。目标 2 将确定 28 天的 APM 输注对产生癫痫发作和致死所需的可卡因剂量（分别为 ED50 和表观 LD50）的影响。目标 3 将确定目标 1 中发现增加的受体的选择性拮抗剂是否会减弱目标 2 中观察到的对可卡因敏感性的任何改变。结果将确定哪些受体发生了改变以及对可卡因毒性的敏感性与这些受体变化有何关系。该实验将模拟服用 APM 的患者急性使用可卡因的情况。识别所涉及的受体系统将有助于未来的研究，以确定长期 APM 治疗是否会在人类中引起相同的受体变化，从而可能导致类似的可卡因中毒易感性改变。