Implantable Minipump For Tetherless Drug Self-Administration In Mice

描述(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障碍之一。用于评价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给药。在这些范例中，拴系重塑“正常”行为的程度可能是相当大的。已经非常清楚的是，就像在人类群体中一样，自我给药的相对增强强度对环境操纵高度敏感，其中许多很难用拴系的动物建模。系绳只适用于研究动物在隔离状态下的行为，仅限于动物与缆绳缠绕的风险较低的行为的子集。由于药物自我给药对压力和环境因素的敏感性，需要更多的“自然主义”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在目前的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。我们的跨学科团队寻求：(1)开发一种可植入的微泵，使药物自我给药小鼠能够无绳、重复给药。目前，还没有这样的设备商业化。在泵中，药物通过电解产生的气体驱动的横隔膜的位移来给药，并由感应功率传递提供动力；(2)设计和制造泵的行为笼形接口，以便于泵在临床前给药研究中的使用。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，它触发感应能量转移到电解泵，(3)在小鼠静脉注射可卡因的过程中测试无绳输液系统。按需，无系绳给药(A)有望为研究当前转基因小鼠模型中的成瘾行为开辟新的途径，(B)减少压力并消除导管缠绕的风险，从而便于检查药物自我给药对社会、母体和交配行为的影响，以及丰富的环境对药物使用的影响，(C)允许对成瘾潜力较低的药物进行24小时静脉给药，其中需要动物过夜暴露以建立药物自我给药，(D)可以很容易地改装为提供大脑内给药，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，如非人类灵长类动物，(E)提供一种独特的实验工具，其应用范围超出药物成瘾领域，应用于药理学、动物行为和生理学领域。公共卫生相关性：自我给药滥用药物的相对强化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、自含式的微泵，用于在小鼠药物自我给药模型中按需、无绳给药。这个实验工具将允许检查复杂的行为(例如，社会行为、母亲行为)和复杂的环境对成瘾的影响。它在转基因小鼠模型中的应用将允许检查基因x环境交互作用，这对于解释基因对人类受试者成瘾行为的影响范围和限度是至关重要的。

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.