Acute and Chronic Effects of Inhalants in ICSS

吸入剂对 ICSS 的急性和慢性影响

• 批准号: 8822849
• 负责人: Matthew E Tracy
• 金额: $ 3.45万
• 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/8822849
• 关键词: Abstinence; Acute; Address; Adolescent; Adult; Agonist; Air; Anhedonia; Animal Model; Anxiety; 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; anxiety-like behavior; drug of abuse; gamma-Aminobutyric Acid; in vivo; inhalation drug abuse; male; median forebrain bundle; pre-clinical; 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）：吸入剂是一组庞大且多样化的物质，其定义不严格，可通过给药途径来定义。尽管有明确的科学证据表明鼻吸剂对人类健康有不利影响，但滥用鼻吸剂仍然是一个世界性的医学问题。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，这些程序模拟成瘾过程的不同方面。本提案将调查基本行为程序，以评估在这些程序中两种原型吸入剂（甲苯和一氧化二氮）的滥用相关影响。我们的第一个目标将是检查这些吸入剂的急性奖励作用。两组16只C57 BL 6/J小鼠将在其内侧前脑束中植入慢性双极电极。然后训练小鼠在空气暴露条件下对电刺激作出反应。在建立基线后，一半小鼠将暴露于增加或减少浓度的甲苯或一氧化二氮，同时允许对ICSS作出反应。通过检查ICSS频率-反应曲线的变化、反应的渐进比率时间表和最终基线阈值变化来评估ICSS的奖励效应的变化。机制上，我们将探讨GABA和NMDA介导的促进ICSS的预处理与选择性药物阻断促进的贡献。与滥用相关的依赖和戒断效应，如快感缺失和焦虑，是成瘾的关键组成部分。因此，我们将检查从长期吸入性暴露中戒断是否产生快感缺失效应（通过ICSS阈值变化测量）和焦虑样效应（通过高架十字迷宫和亮/暗盒探索中的表现测量）。三组16只C57 BL 6/J小鼠将植入慢性双极ICSS电极，并训练对ICSS的反应直至稳定。然后将小鼠暴露于甲苯或一氧化二氮中10天，每天24小时，浓度略低于产生明显急性行为效应的浓度。第三组将作为对照，仅在相同条件下暴露于空气中。在随后的停药期内，将在停止吸入剂暴露后4、8、24和48小时测定ICSS阈值。在每次ICSS治疗后，还将检查高架十字迷宫和明/暗盒性能。最后，我们将检查吸入剂产生的大脑奖励回路的持续变化，这被认为是复发的主要因素，将检查慢性暴露研究中使用的相同小鼠因慢性暴露而导致的ICSS表现的长期变化。每天在空气暴露条件下进行ICSS测试，并与慢性吸入剂暴露前生成的ICSS频率响应曲线以及空气对照组进行比较。我们相信，该项目对人类成瘾过程的多个组成部分进行建模，对于更好地理解吸入剂的滥用相关影响以及产生适合于检查吸入剂滥用机制和潜在治疗药物的模型具有很大的希望。