Drug-Induced Allostasis and Its Motivational Effects During Adolescence

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。这项建议调查了一氧化二氮(N2O)诱导的变态反应以及处于变态反应状态的动机后果。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以与控制值显著不同的水平持续发挥作用，潜在地损害个人的健康或生存能力。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，并且这些控制系统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。拟议的研究使用了一种复杂的实验模型，该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(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。初步数据表明，青春期大鼠特别容易发生药物引起的异速生长变化，这表明对异速生长发育的易感性增加可能是青春期对药物成瘾易感性增加的关键病因。特定目标(SA)1比较了青春期和成年大鼠在不同N2O浓度范围内的同素平衡发育，确定这些同素平衡过程是否稳定，并探索如何消除这些过程。SA 2比较了一系列N2O浓度对青春期和成年大鼠的热刺激效应，并评估了青春期变态平衡状态的动力效应。此外，还将探讨初始敏感性、同素抑制发展和N2O自我给药行为之间的关系。SA 3考察了在不平衡状态下测量的因素(N2O浓度、核心温度、热损失、热产生)是否可以用作动机行为的预测因子。这项工作对于了解药物成瘾的机制具有重要的现实意义和理论意义。这项拟议的研究还增加了调查青春期可滥用吸入剂的相关性，NIH已将其确定为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。这项拟议的研究使用了一种研究不足的吸入剂来研究发育时期(青春期)药物诱导的异物作用，该时期以对药物成瘾的高度敏感性而闻名。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. 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.