Advancing the Understanding of Drug-Induced Allostasis

描述(申请人提供)：长期服药会产生异位，这是一种与药物耐受性有关的不适应状态。反复给予一氧化二氮(N2O)可引起体内恒温调节状态，体内热量产生和损失失衡，但其生理机制尚不清楚。这项小额拨款申请建议研究N2O诱导的变态变化以及单个效应器系统如何相互作用来产生变态。异位平衡是指一种无序的稳态调节形式，其中被调节的变量或其一个或多个控制决定因素持续发挥作用，其水平与控制值不同，潜在地损害个人的健康或生存能力。一种药物成瘾的变态模型假设 生物行为控制系统调节与吸毒行为相关的变量，这些控制系统很容易受到药物诱导的变态变化的影响，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(新陈代谢热产生和热释放)，从而能够严格确定重复使用N2O期间的变态动力学。这个体温调节模型系统也提供了一种灵敏的方法来确定同素作用的动机后果。最近的研究和来自我们实验室的初步数据表明，当通常在相反方向上调整受调控变量的值的效应器系统同时激活并彼此相反地工作时，可能会出现异基因现象。提出了两个具体的目标，以促进我们对药物诱导的同素作用的理解。具体目标1将开发和验证红外热像仪作为一种连续和非侵入性方法的使用，以评估两个主要效应系统的活动，即热量产生和因重复给予N2O而导致的异体生长过程中的热量损失。具体地说，热量的产生将根据肩胛骨间棕色脂肪组织的温度和大鼠尾部皮肤温度的热量损失进行评估。具体目标2建议建造和验证一种住在对流型直接热量计，使其能够在长期使用N2O的整个过程中观察核心温度、产热量和热量损失。以前的工作表明，在调节变量的水平上，在异位作用明显之前，在长期的初始N2O给药期间，相反的效应器活动可能变得明显。由于我们的小型直销施加的大小限制 在热量计室中，研究延长的稳态N2O给药过程中热量产生和热量损失相互作用的动力学一直是不可行的。这项工作对于了解药物诱导的异物抑制和成瘾的机制具有重要的理论和实践意义。拟议的研究还增加了调查可滥用吸入剂的相关性，这是一个重要但未得到充分研究的研究领域。 与公共健康相关：一种被称为异位平衡的动态平衡失调形式被认为在药物成瘾的发展中起到病因学作用。这项拟议的研究使用了一种未被充分研究的吸入剂--一氧化二氮，来研究药物诱导的同素作用以及导致其发展的过程。这一研究结果将有助于我们了解药物成瘾的发病机制和治疗方法。

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.