Drug-Induced Allostasis and Its Motivational Effects During Adolescence

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。该建议调查一氧化二氮（N2O）诱导的非稳态变化和非稳态状态下的动机后果。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显著不同于对照值的水平上持续发挥作用，从而潜在地损害个体的健康或生存能力。药物成瘾的适应性模型认为，生物行为控制系统调节与吸毒行为相关的变量，这些控制系统容易受到药物诱导的适应性变化的影响，从而促进成瘾的发展。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，以便可以同时测量核心温度及其决定因素（代谢产热和放热），从而能够在重复N2O给药期间严格确定非稳态动力学。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。初步数据表明，青春期大鼠特别容易发展药物诱导的变稳态的变化，这表明增加的易感性变稳态发展可能是一个关键的病因因素，在青春期的药物成瘾的高度脆弱性。特定目标（SA）1比较了在一系列N2O浓度下青少年与成年大鼠的变稳态发展，确定这些变稳态过程是否稳定，并探讨它们如何被熄灭。SA 2比较了青少年与成年大鼠中一系列N2O浓度的热激励效应，并评估了青春期非稳态状态的激励效应。此外，初始敏感性，别稳态发展和N2O自我管理行为之间的关系将进行调查。SA 3检查在非稳态状态下测量的因素（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。这项工作对于理解药物成瘾的机制具有重要的理论和实践意义。拟议的研究增加了调查青少年时期滥用吸入剂的相关性，NIH已将其确定为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怀疑在药物成瘾的发展中起病因作用。这项拟议的研究使用了一种未充分研究的吸入剂来调查发育期（青春期）药物诱导的变稳态，该发育期以其对药物成瘾的高度敏感性而闻名。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.