Advancing the Understanding of Drug-Induced Allostasis

描述（由申请方提供）：长期给药可产生别稳态，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）导致坦率的施用内变稳态体温调节状态，其基础是身体热量产生和损失之间的不平衡，但生理机制尚不确定。这个小补助金申请提出研究N2O诱导的非稳态变化以及个体效应系统如何相互作用以产生非稳态状态。变应性是指稳态调节的紊乱形式，其中受调节的变量或其控制决定因素中的一种或多种在与对照值不同的水平上持续发挥作用，从而可能损害个体的健康或生存能力。一个药物成瘾的自动调节模型假设， 生物行为控制系统调节与吸毒行为相关的变量，这些控制系统易受药物诱导的非稳态变化的影响，这些变化促进成瘾的发展。我们的实验室使用了一个复杂的实验模型，结合了直接和间接量热法，使核心温度及其决定因素（代谢产热和放热）可以同时测量，使严格的非稳态动力学确定在重复N2O管理。这个体温调节模型系统也提供了一个敏感的方法来确定非稳态的动机后果。最近的研究和我们实验室的初步数据表明，当效应器系统通常以相反的方向调节调节变量的值时，可能会导致变稳态，同时变得活跃，并且彼此相反地工作。提出了两个具体的目标，这将促进我们对药物诱导的变稳态的理解。具体目标1将开发和验证红外热成像作为一种连续和非侵入性的方法，用于评估两个主要效应系统的活性，用于在重复N2O给药导致的变稳态发展过程中产生热量和损失热量。具体而言，将根据肩胛间棕色脂肪组织温度和大鼠尾部皮肤温度的热损失评估产热。具体目标2建议建立和验证一个生活在对流型直接热量计，这将使人们有可能观察核心温度，热量产生和热量损失在整个长期的一氧化二氮管理。以前的工作表明，相反的效应活动可能会变得明显，在长期的初始N2O管理之前，变平衡是明显的调节变量的水平。由于我们的小型直销店尺寸限制， 热量计室，它一直是不可行的，以研究如何产热和热损失的动态相互作用，在一个长期的稳态N2O管理。本工作对于理解药物诱导的变稳态和成瘾的机制具有重要的理论和实践意义。拟议的研究还与调查可滥用的吸入剂有关，这是一个重要但研究不足的研究领域。 公共卫生相关性：一种被称为变稳态的稳态失调形式被认为在药物成瘾的发展中起着病因学作用。拟议的研究使用一种未充分研究的吸入剂一氧化二氮来研究药物诱导的变稳态及其发展过程。本研究的发现将有助于我们对药物成瘾的发病机制和治疗的理解。

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.