Implantable Minipump For Tetherless Drug Self-Administration In Mice

描述（由申请人提供）：就个人悲剧和整体社会经济负担而言，药物成瘾仍然是最昂贵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的药物自我给药范式主要依赖于拴系动物的静脉给药。在这些范例中，拴绳重塑“正常”行为的程度可能是实质性的。已经非常清楚的是，就像在人类中一样，自我给药的相对强化强度对环境操纵高度敏感，其中许多很难用拴着的动物来模拟。拴绳法仅适用于研究孤立动物的行为，而且仅限于研究动物被拴绳缠住的风险较低的行为子集。由于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尤为重要。我们的跨学科团队寻求：(1)开发一种可植入的微型泵，为自我给药的小鼠提供无系绳、重复给药。目前，这种设备还没有商业化。在泵中，药物通过电解产生的气体驱动隔膜的位移来给药，并由感应功率传输供电。(2)为泵设计和制造一个行为笼接口，以方便泵在药物自我给药的临床前研究中使用。在这个笼子里，自我给药是由一个特定的动物行为（杠杆按压）启动的，该行为触发感应功率转移到电解泵，(3)在小鼠静脉内自我给药期间测试无绳输注系统。按需、无绳给药(a)有望为当前转基因小鼠模型的成瘾行为研究开辟新的途径，(b)减轻压力并消除导管缠结的风险，从而便于研究药物自我给药对社会、母系和交配行为的影响，以及丰富的环境对药物使用的影响，(c)允许24小时静脉内自我给药，以获得较低成瘾潜力的药物。在需要对动物进行夜间暴露以建立药物自我给药的情况下，(d)可以很容易地适应于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，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，可用于药理学，动物行为和生理学领域。公共卫生相关性：自我滥用药物的相对强化强度对环境操纵高度敏感，但目前的临床前模型涉及拴在外部机械输注泵上的动物，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、自包含的微型泵，用于按需、无系绳给药小鼠模型。这个实验工具将允许检查复杂行为（如社会行为、母性行为）和复杂环境对成瘾的影响。它在转基因小鼠模型中的应用将允许检查基因与环境的相互作用，这对于解释人类受试者成瘾行为的遗传影响的范围和限制至关重要。

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.