Drug-Induced Allostasis and Its Motivational Effects During Adolescence

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。本研究探讨了氧化亚氮（N2O）诱导的适应变化和处于适应状态的动机后果。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与控制值显著不同的水平起作用，可能损害个体的健康或生存能力。药物成瘾的适应调节模型假设生物行为控制系统调节与药物服用行为相关的变量，并且这些控制系统容易受到药物诱导的促进成瘾发展的适应调节变化的影响。拟议的研究使用了一个复杂的实验模型，该模型结合了直接和间接量热法，以便同时测量核心温度及其决定因素（代谢产热和热释放），从而能够严格确定重复N2O处理期间的适应动力学。这种体温调节模型系统也提供了一种灵敏的方法来确定适应平衡的动机后果。初步数据表明，青春期大鼠特别容易发生药物诱导的适应变化，这表明对适应变化的易感性增加可能是青春期对药物成瘾的易感性增加的关键病因因素。特异性目的（SA） 1比较了青春期大鼠和成年大鼠在N2O浓度范围内的适应过程，确定这些适应过程是否稳定，并探讨了它们如何被消灭。SA 2比较了青春期和成年大鼠中一系列N2O浓度的热激励效应，并评估了青春期适应状态的激励效应。此外，我们还将研究初始敏感性、失衡发展与N2O自我给药行为之间的关系。SA 3检验在适应状态下测量的因素（N2O浓度、核心温度、热损失、产热）是否可以用作动机行为的预测因子。这项工作对理解药物成瘾的机制具有实践和理论意义。拟议的研究具有调查青少年时期滥用吸入剂的附加相关性，NIH已确定这是一个重要但尚未充分研究的研究领域。公共卫生相关性：一种被称为异稳态的体内平衡失调形式被怀疑在药物成瘾的发展中起病因学作用。拟议的研究使用一种未充分研究的吸入剂来研究发育时期（青春期）药物诱导的异稳态，这一时期因其对药物成瘾的高度易感性而闻名。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. This proposal investigates nitrous oxide (N2O)-induced allostatic changes and the motivational consequences of being in an 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 significantly different from control values, potentially 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. The proposed studies use 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. Preliminary data indicate that adolescent rats are especially prone to develop drug-induced allostatic changes, suggesting that increased susceptibility to allostasis development may be a critical etiological factor for the heightened vulnerability to drug addiction during adolescence. Specific Aim (SA) 1 compares allostasis development in adolescent versus mature rats over a range of N2O concentrations, determines whether these allostatic processes stabilize, and explores how they can be extinguished. SA 2 compares the thermally motivated effects of a range of N2O concentrations in adolescent versus mature rats and assesses the motivational effects of an allostatic state during adolescence. In addition, the relationship between initial sensitivity, allostasis development and N2O self-administration behavior will be investigated. SA 3 examines whether factors measured in the allostatic state (N2O concentration, core temperature, heat loss, heat production) can be used as predictors of motivated behavior. This work has practical and theoretical importance for understanding the mechanisms underlying drug addiction. The proposed research has the added relevance of investigating an abusable inhalant during the adolescent period which NIH has identified as an important, yet understudied, research area. PUBLIC HEALTH RELEVANCE: A form of homeostatic dysregulation known as allostasis is suspected to play an etiologic role in the development of drug addiction. The proposed research uses an understudied inhalant to investigate drug-induced allostasis during a developmental period (adolescence) that is known for its heightened susceptibility to drug addiction. The findings of this research will contribute to our understanding of the pathogenesis and treatment of drug addiction.