Advancing the Understanding of Drug-Induced Allostasis

描述（由申请人提供）：长期给药可产生适应平衡，一种与药物耐受性相关的不适应状态。反复给药一氧化氮（N2O）可导致体内热产生和热损失之间的不平衡导致体内热调节状态，但生理机制尚不确定。这项小额拨款申请旨在研究N2O诱导的适应性变化以及单个效应系统如何相互作用以产生适应性状态。异稳态是指体内平衡调节的一种紊乱形式，其中一个被调节变量或其一个或多个控制决定因素持续以不同于控制值的水平起作用，从而潜在地损害个体的健康或生存能力。一种药物成瘾的适应性模型认为

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.