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: 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
• 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

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职业发展奖将为医学博士肯农·希尔德助理教授提供受保护的时间，使他能够获得基本研究培训和经验，这是他成为一名成功的专注于药物滥用中毒的独立调查员所需的。作为一名急诊医生和医学毒物学家，希尔德博士每天都会遇到急性滥用药物中毒的患者。作为一名独立研究员，他的长期目标是评估针对这种急性中毒的新疗法。他将与他的赞助人南希·R·扎尼瑟博士密切合作，南希·R·扎尼瑟博士是一名经验丰富的可卡因研究人员，已成功指导了20名研究生和研究生实习生。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药理学和负责任的研究指导方面的研究生课程，以及完成一个帮助他发展有效指导技能的项目。他提出的研究项目源于这样一个观察：尽管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的影响知之甚少。一个小鼠模型将被用来研究长期服用抗精神病药物(ARM)对单次高剂量可卡因毒性效应的影响。可卡因阻断了所有三种单胺转运体，长期给药会增加几种神经递质受体的密度。希尔德博士假设，长期服用特定的APM将不同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28天的小鼠的局部受体和单胺转运体密度。体外放射配基结合和放射自显影将被用来测量D_1和D_2多巴胺，5-羟色胺1，5-羟色胺2，5-羟色胺2C和5-羟色胺3，1和2肾上腺素能，NMDA和AMPA谷氨酸，GABAA，M胆碱能，以及Sigma受体和单胺转运体的区域密度。目的2将确定28天注射APM对导致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。AIM 3将确定在AIM 1中发现增加的受体的选择性拮抗剂是否会减弱在AIM 2中观察到的对可卡因的任何改变的敏感性。结果将确定哪些受体发生改变，以及对可卡因毒性的敏感性如何与这些受体的变化有关。这项实验将模拟服用APM的患者的急性可卡因使用。识别涉及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敏感性改变。