Implantable Minipump For Tetherless Drug Self-Administration In Mice

用于小鼠无绳自我给药的植入式微型泵

基本信息

批准号：
7708484
负责人：
DANIEL PHILIPP HOLSCHNEIDER
金额：
$ 16.3万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7708484
关键词：
Acute Addictive Behavior Address Aggressive behavior Alcohol consumption Animal Behavior Animal Model Animals Area Behavior Behavioral Bolus Infusion Brain Catheters Chronic Cocaine Complex Consumption Devices Disease Dose Drug Addiction Drug Controls Drug Delivery Systems Drug Sensitization Drug usage Economic Burden Electrolyses Environment Environmental Risk Factor Evaluation Face Gases Genes Genetic Hormones Hour Human Implant Implantable Pump Infusion Pumps Infusion procedures Intake Intravenous Laboratories Maternal Behavior Mechanics Methods Modeling Motor Mus Opiates Oral Partner in relationship Pharmaceutical Preparations Pharmacology Physical Dependence Physiology Play Population Pre-Clinical Model Procedures Pump Relapse Relative (related person)Research Respiratory Diaphragm Risk Role Route Self Administration Self-Administered Social Behavior Stress System Testing Transgenic Mice Upper arm Validation addiction design drug of abuse drug sensitivity human subject in vivo insight mouse model neuropsychiatry nonhuman primate pre-clinical pre-clinical research preclinical study public health relevance response social tool

项目摘要

DESCRIPTION (provided by applicant): Drug addiction remains among the most costly neuropsychiatric disorders in terms of personal tragedy and overall societal economic burden. Drug self-administration paradigms in preclinical animal models for the evaluation of stimulant and opiate drugs have relied primarily on intravenous drug administration in tethered animals. The extent to which tethering reshapes 'normal' behavior in these paradigms is likely substantial. What has become abundantly clear is that, as in the human population, the relative reinforcing strength of self- administered drugs is highly sensitive to environmental manipulations, many of which are difficult to model using tethered animals. Tethering is practical only in the study of behaviors of animals in isolation and is limited to a subset of behaviors, which present a low risk of entanglement of the animal with its cable. Because of the sensitivity of drug self-administration to stress and environmental factors, more 'naturalistic' settings are needed to study addictive behavior. This is particularly relevant in understanding the role played by genes in addiction and the importance of gene x environment interactions in current transgenic mouse models. Our interdisciplinary team seeks: (1) to develop an implantable minipump to allow tetherless, repeated drug delivery for drug self-administration mice. Currently, no such device is available commercially. In the pump, drug is administered by the displacement of a diaphragm driven by gas generated from electrolysis and powered by inductive power transfer, (2) to design and fabricate a behavioral cage interface for the pump to facilitate the use of the pump in preclinical studies of drug self-administration. In this cage, self-administration is initiated by a specific animal behavior (lever press) which triggers inductive power transfer to the electrolytic pump, (3) to test the tetherless infusion system in mice during the intravenous self-administration of cocaine. On-demand, tetherless drug delivery (a) promises to open new avenues for the study of addictive behavior in current transgenic mouse models, (b) reduces stress and eliminates the risk of catheter entanglement, thereby facilitating examination of the effects drug self-administration has on social, maternal and mating behaviors, as well as the effects enriched environments have on drug use, (c) allows 24 hour access to intravenous drug self-administration for drugs of lower addictive potential, where overnight exposure of an animal is needed to establish drug self-administration, (d) can be easily adapted to provide intracerebral administration for testing of the role of specific brain areas in addiction behavior, or scaled to other animal models of drug addiction such as nonhuman primates, (e) provides a unique experimental tool whose applications extend beyond the field of drug addiction for applications in the fields of pharmacology, animal behavior, and physiology. PUBLIC HEALTH RELEVANCE: The relative reinforcing strength of self-administered drugs of abuse is highly sensitive to environmental manipulations, yet current preclinical models involve animals tethered to external mechanical infusion pumps and do not allow significant exploration of the effects of environmental factors on addictive behavior. We propose the fabrication and validation of an implantable, self-contained minipump for on-demand, tetherless drug-delivery in mouse models of drug self-administration. This experimental tool will allow examination of the effects of complex behaviors (e.g. social behavior, maternal behavior) and complex environments on addiction. Its application in transgenic mouse models will allow examination of gene x environment interactions, which are crucial to the interpretation of the range and limits of genetic influences on addictive behaviors in human subjects.

描述（由申请人提供）：就个人悲剧和整体社会经济负担而言，吸毒成瘾仍然是代价最高的神经精神疾病之一。用于评估兴奋剂和阿片类药物的临床前动物模型中的药物自我给药范例主要依赖于拴系动物的静脉内给药。在这些范式中，束缚重塑“正常”行为的程度可能是巨大的。已经非常清楚的是，就像在人类中一样，自我给药药物的相对增强强度对环境操作高度敏感，其中许多操作很难使用拴系动物进行建模。拴系仅在研究孤立动物的行为时才实用，并且仅限于行为的子集，这些行为的动物与其电缆纠缠的风险较低。由于药物自我给药对压力和环境因素的敏感性，需要更“自然”的环境来研究成瘾行为。这对于理解基因在成瘾中所起的作用以及当前转基因小鼠模型中基因与环境相互作用的重要性特别相关。我们的跨学科团队致力于：(1) 开发一种植入式微型泵，以允许小鼠自行给药时进行无绳、重复的药物输送。目前，此类设备还没有商用。在泵中，药物通过由电解产生的气体驱动并由感应功率传输供电的隔膜的位移来施用，(2)为泵设计和制造行为笼接口，以促进在临床前研究中使用泵药物的自我给药。在这个笼子里，自我给药是由特定的动物行为（杠杆按压）启动的，这会触发感应功率传输到电解泵，（3）在静脉自我给药可卡因期间测试小鼠的无绳输注系统。按需、无绳药物输送（a）有望为当前转基因小鼠模型的成瘾行为研究开辟新途径，（b）减轻压力并消除导管缠结的风险，从而促进药物自我给药效果的检查(c) 允许对成瘾潜力较低的药物进行 24 小时静脉内自我给药，其中过夜暴露于需要动物来建立药物自我给药，（d）可以很容易地适应提供脑内给药，以测试特定大脑区域在成瘾行为中的作用，或扩展到其他药物成瘾动物模型，例如非人类灵长类动物，（e ）提供了一种独特的实验工具，其应用范围超出了药物成瘾领域，应用于药理学、动物行为和生理学领域。公共健康相关性：自我施用滥用药物的相对增强强度对环境操作高度敏感，但目前的临床前模型涉及拴在外部机械输液泵上的动物，不允许对环境因素对成瘾行为的影响进行重大探索。我们建议制造和验证一种可植入的、独立的微型泵，用于在药物自我给药模型中按需、无绳输送药物。该实验工具将允许检查复杂行为（例如社会行为、母亲行为）和复杂环境对成瘾的影响。其在转基因小鼠模型中的应用将允许检查基因与环境的相互作用，这对于解释遗传对人类受试者成瘾行为的影响范围和限制至关重要。