Acute and Chronic Effects of Inhalants in ICSS

吸入剂对 ICSS 的急性和慢性影响

• 批准号: 8527150
• 负责人: Matthew E Tracy
• 金额: $ 3.36万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-10 至 2016-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527150
• 关键词: Abstinence; Acute; Address; Adolescent; Adult; Agonist; Air; Anhedonia; Animal Model; Anxiety; Behavior; Behavioral; Biological Assay; Boxing; Brain; Characteristics; Chronic; Cocaine; Control Groups; Data; Dependence; Diazepam; Dose; Drug usage; Electric Stimulation; Electrodes; Exposure to; Face; Frequencies; Future; GABA Receptor; Glues; Goals; Health; Hour; Human; Implant; In Vitro; Individual; Inhalant dose form; Intravenous; Life; Light; Literature; Measures; Mediating; Medical; Modeling; Molecular Genetics; Motivation; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurotransmitters; Nitrous Oxide; Paint; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Procedures; Process; Property; Publishing; Rattus; Relapse; Research; Rewards; Risk; Route; Schedule; Self Administration; Self Stimulation; Solutions; Surveys; System; Testing; Time; Toluene; Training; Withdrawal; addiction; drug of abuse; gamma-Aminobutyric Acid; in vivo; inhalation drug abuse; male; median forebrain bundle; pre-clinical; public health relevance; receptor; response; reward circuitry; reward processing; success; tool

DESCRIPTION (provided by applicant): Inhalants are a large and diverse group of substances loosely defined by route of administration. Despite clear scientific evidence of their negative effects on human health, the abuse of inhalants remains a worldwide medical problem. Predicting whether an inhalant will be abused as well as developing treatments for inhalant abuse requires suitable experimental procedures which model different aspects of the addiction process. This proposal will investigate basic behavioral procedures for assessing abuse-related effects of two prototypic inhalants in these procedures: toluene and nitrous oxide. Our first goal will be to examine the acute rewarding effects of these inhalants. Two groups of 16 C57BL6/J mice will be implanted with chronic bipolar electrodes into their medial forebrain bundle. Mice will then be trained to respond for electrical stimulation under air exposure conditions. After a baseline has been established half the mice will be exposed to increasing or decreasing concentrations of toluene or nitrous oxide while being allowed to respond for ICSS. Changes in the rewarding effects of ICSS will be assessed both by examining shifts in ICSS frequency-response curve, a progressive ratio schedule of responding, and finally baseline threshold shifts. Mechanistically we will explore the contribution of both GABA and NMDA mediated facilitation of ICSS by pretreatment with selective agents to block facilitation. Dependence and withdrawal effects associated with abuse such as anhedonia and anxiety are critical components of addiction. Therefore we will examine if withdrawal from chronic inhalant exposure produces anhedonic effects as measured by changes in ICSS thresholds and anxiety-like effects as measured by performance in an elevated plus maze and light/dark box exploration. Three groups of 16 C57BL6/J mice will be implanted with chronic bipolar ICSS electrodes and trained to respond for ICSS until stable. The mice will then be exposed to 10 days of 24 hour/day exposure to toluene or nitrous oxide at a concentration just below that which produces overt acute behavioral effects. The third group will serve as a control and only be exposed to air under identical conditions. During the subsequent withdrawal period, ICSS thresholds will be determined at 4, 8, 24 and 48 hours after discontinuing inhalant exposure. Elevated plus maze and light/dark box performance will also be examined after each ICSS session. Lastly, we will examine persistent changes in brain reward circuitry produced by inhalants which are believed to be a major factor in relapse, the same mice used in the chronic exposure study will be examined for long-term changes in ICSS performance as a result of chronic exposure. ICSS tests will be conducted daily under air exposure conditions and compared to the ICSS frequency-response curves generated prior to chronic inhalant exposure as well as to the air control group. We believe that this project which models multiple components of the addiction process in humans has great promise for better understanding the abuse-related effects of inhalants as well as producing a model suitable for the examination of the mechanism(s) and potential treatment medications for inhalant abuse.

描述（由申请人提供）：吸入剂是一大类不同的物质，按给药途径进行了松散的定义。尽管有明确的科学证据表明吸入剂对人类健康有负面影响，但吸入剂的滥用仍然是一个世界范围的医学问题。预测吸入剂是否会被滥用以及开发吸入剂滥用的治疗方法需要适当的实验程序来模拟成瘾过程的不同方面。该提案将研究基本行为程序，以评估这些程序中两种原型吸入剂（甲苯和一氧化二氮）与滥用相关的影响。我们的首要目标是检查这些吸入剂的急性奖励作用。两组 16 只 C57BL6/J 小鼠将被植入慢性双极电极到它们的内侧前脑束中。然后将训练小鼠在暴露于空气的条件下对电刺激做出反应。建立基线后，一半的小鼠将暴露于浓度升高或降低的甲苯或一氧化二氮，同时允许对 ICSS 做出反应。 ICSS 奖励效果的变化将通过检查 ICSS 频率响应曲线的变化、响应的渐进比例表以及最后的基线阈值变化来评估。从机制上讲，我们将通过用选择性试剂进行预处理来阻断促进作用来探索 GABA 和 NMDA 介导的 ICSS 促进作用。与滥用相关的依赖性和戒断效应，例如快感缺乏和焦虑，是成瘾的关键组成部分。因此，我们将检查从慢性吸入暴露中戒断是否会产生快感缺失效应（通过 ICSS 阈值的变化来衡量）和焦虑样效应（通过高架十字迷宫和明暗盒探索的表现来衡量）。三组 16 只 C57BL6/J 小鼠将被植入慢性双极 ICSS 电极，并接受训练以对 ICSS 做出反应直至稳定。然后，小鼠将连续 10 天每天 24 小时接触甲苯或一氧化二氮，其浓度略低于产生明显的急性行为影响的浓度。第三组将作为对照，并且仅在相同条件下暴露于空气中。在随后的停药期内，ICSS 阈值将在停止吸入暴露后 4、8、24 和 48 小时确定。每次 ICSS 会议后还将检查高架十字迷宫和明暗箱性能。最后，我们将检查吸入剂产生的大脑奖赏回路的持续变化，这被认为是复发的主要因素，慢性暴露研究中使用的相同小鼠将检查因慢性吸入剂导致的 ICSS 表现的长期变化。接触。 ICSS 测试将在空气暴露条件下每天进行，并与慢性吸入暴露之前生成的 ICSS 频率响应曲线以及空气对照组进行比较。我们相信，这个对人类成瘾过程的多个组成部分进行建模的项目对于更好地了解吸入剂与滥用相关的影响以及产生适合检查吸入剂的机制和潜在治疗药物的模型具有很大的希望。虐待。