Advancing the Understanding of Drug-Induced Allostasis

描述（由申请人提供）：长期用药会产生异稳态，这是一种与药物耐受性相关的适应不良状态。重复施用一氧化二氮（N2O）会导致体内热量产生和损失之间不平衡，从而导致明显的给药内温度调节状态，但其生理机制尚不确定。这项小额资助申请旨在研究 N2O 引起的稳态变化以及各个效应器系统如何相互作用以产生稳态状态。动态平衡是指稳态调节的一种无序形式，其中受调节变量或其一个或多个控制决定因素持续以不同于对照值的水平发挥作用，可能损害个体的健康或活力。毒瘾的变稳态模型假设 生物行为控制系统调节与吸毒行为相关的变量，并且这些控制系统容易受到药物引起的稳态变化的影响，从而促进成瘾的发展。我们的实验室使用复杂的实验模型，结合了直接和间接量热法，以便可以同时测量核心温度及其决定因素（代谢产热和放热），从而能够在重复 N2O 给药期间严格确定动态变化。该体温调节模型系统还提供了一种灵敏的方法来确定动态平衡的动机后果。我们实验室的最新研究和初步数据表明，当通常以相反方向调整调节变量值的效应系统变得同时活跃并彼此相反地工作时，就会产生动态平衡。提出了两个具体目标，这将增进我们对药物诱导的动态平衡的理解。具体目标 1 将开发和验证红外热成像作为一种连续且非侵入性的方法，用于评估由于重复 N2O 给药而导致的动态平衡发展过程中两个主要效应系统的产热和热损失的活性。具体而言，将根据肩胛间棕色脂肪组织温度评估产热，并根据大鼠尾部皮肤温度评估热损失。具体目标 2 建议建造并验证一种现场对流型直接量热计，以便在长时间 N2O 管理过程中观察核心温度、产热和热损失。先前的研究表明，在调节变量水平出现明显的平衡之前，在长时间的初始 N2O 给药过程中，相反的效应器活性可能会变得明显。由于我们的小型直接施加的尺寸限制 在热量计室中，研究在长期稳态 N2O 管理期间产热和热损失如何相互作用的动力学尚不可行。这项工作对于理解药物引起的动态平衡和成瘾的机制具有实际和理论意义。拟议的研究还与调查可滥用吸入剂有关，这是一个重要但尚未得到充分研究的研究领域。 公共卫生相关性：一种被称为动态平衡的稳态失调被认为在药物成瘾的发展中发挥着病因作用。拟议的研究使用一种尚未研究的吸入剂一氧化二氮来研究药物诱导的动态平衡及其发展过程。这项研究的结果将有助于我们了解毒瘾的发病机制和治疗。

DESCRIPTION (provided by applicant): Chronic drug administration can produce allostasis, a maladaptive state related to drug tolerance. Repeated administrations of nitrous oxide (N2O) lead to a frank intra-administration allostatic thermoregulatory state underlain by an imbalance between body heat production and loss, but the physiologic mechanisms are uncertain. This small-grant application proposes to investigate N2O -induced allostatic changes and how individual effector systems interact to produce the allostatic state. Allostasis refers to a disordered form of homeostatic regulation wherein a regulated variable, or one or more of its controlling determinants, persistently functions at levels different from control values, potentialy compromising an individual's health or viability. An allostatic model of drug addiction posits that biobehavioral control systems regulate variables relevant to drug taking behavior and that these control systems are vulnerable to drug-induced allostatic changes which promote the development of addiction. Our laboratory uses a sophisticated experimental model that combines direct and indirect calorimetry so that core temperature and its determinants (metabolic heat production and heat release) can be simultaneously measured, enabling rigorous determination of allostatic dynamics during repeated N2O administrations. This thermoregulatory model system also provides a sensitive method for determining the motivational consequences of allostasis. Recent research and preliminary data from our laboratory suggest that allostasis can result when effector systems that normally adjust a regulated variable's value in opposite directions become concurrently active and work in opposition with one another. Two specific aims are proposed that will advance our understanding of drug-induced allostasis. Specific Aim 1 will develop and validate the use of infrared thermography as a continuous and non-invasive method for assessing the activity of two major effector systems for heat production and heat loss during allostasis development resulting from repeated N2O administrations. Specifically, heat production will be assessed from interscapular brown adipose tissue temperature and heat loss from the rat's tail skin temperature. Specific Aim 2 proposes to build and validate a live-in convection type direct calorimeter that will make it possible to observe core temperature, heat production and heat loss throughout long duration N2O administrations. Previous work suggests that opposing effector activity may become apparent during a prolonged initial N2O administration before allostasis is evident at the level of the regulated variable. Due to size limitations imposed by our small direct calorimeter chambers, it has not been feasible to study the dynamics of how heat production and heat loss interact during an extended steady-state N2O administration. This work has practical and theoretical importance for understanding the mechanisms underlying drug-induced allostasis and addiction. The proposed research has the added relevance of investigating an abusable inhalant which is an important, yet understudied, research area. PUBLIC HEALTH RELEVANCE: A form of homeostatic dysregulation known as allostasis is thought to play an etiologic role in the development of drug addiction. The proposed research uses an understudied inhalant, nitrous oxide, to investigate drug- induced allostasis and the processes responsible for its development. The findings of this research will contribute to our understanding of the pathogenesis and treatment of drug addiction.