Drug-Induced Allostasis and Its Motivational Effects During Adolescence

青春期药物诱导的动态平衡及其激励作用

基本信息

批准号：
8267064
负责人：
Douglas S Ramsay
金额：
$ 33.71万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267064
关键词：
Accounting Adolescence Adolescent Animals Area Behavior Behavior Control Behavioral Biological Models Blood Brain Calorimetry Characteristics Chronic Data Dependence Development Disease Dose Drug Addiction Drug Controls Drug Exposure Drug Tolerance Experimental Models Fever Gases Growth Health Heat Losses Heating Human Indirect Calorimetry Individual Inhalant dose form Intervention Investigation Maintenance Measures Metabolic Methodology Methods Modeling Motivation Natural History Nitrous Oxide Pathogenesis Pharmaceutical Preparations Physiological Play Predisposition Process Publishing Rattus Regression Analysis Regulation Research Role Self Administration Self-Administered Series System Temperature Testing Thermogenesis United States National Institutes of Health Withdrawal Wood material Work addiction allostasis behavior change biobehavior induced hypothermia innovation motivated behavior natural hypothermia research study response

项目摘要

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.

描述（由申请人提供）：慢性药物管理可以产生同性恋，这是与药物耐受性有关的不良适应状态。该提案研究了一氧化二氮（N2O）诱导的同性恋变化和处于同种异体状态的动机后果。 Allostasis是指一个无序的稳态调节形式，其中受监管的变量或其一个或多个控制决定因素在与控制值显着不同，可能损害个人的健康或生存能力。药物成瘾的同种异体模型认为，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同层变化的影响，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的量热法，以便可以同时测量核心温度及其决定因素（代谢产生和热量释放），从而在重复的N2O施用过程中严格确定同层动力学。该热调节模型系统还提供了一种敏感方法来确定Allostasis的动机后果。初步数据表明，青少年大鼠特别容易发展药物诱导的同性恋变化，这表明增加对Allostasis发育的易感性可能是增强青少年吸毒成瘾脆弱性的关键病因。特定目标（SA）1比较了N2O浓度范围内青少年与成熟大鼠的Allostasis发育，确定这些同层过程是否稳定，并探讨它们如何被熄灭。 SA 2比较了青少年与成熟大鼠的一系列N2O浓度的热动机作用，并评估了青春期同层状态的动机作用。此外，将研究最初的灵敏度，Allostasis发展与N2O自我管理行为之间的关系。 SA 3研究了在同种异体状态下测量的因素（N2O浓度，核心温度，热量损失，产生热量）是否可以用作动机行为的预测指标。这项工作对于理解药物成瘾的机制具有实际和理论上的重要性。拟议的研究具有调查在青少年时期可滥用的吸入剂的附加意义，而NIH已将其确定为一个重要但经过研究的研究领域。公共卫生相关性：一种称为Allostasis的稳态失调形式被怀疑在药物成瘾的发展中起病因。拟议的研究使用研究的吸入剂研究在发育时期（青春期）中研究药物诱导的同性恋，这因其对药物成瘾的敏感性增强而闻名。这项研究的发现将有助于我们理解药物成瘾的发病机理和治疗。