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）：吸入剂是由管理途径宽松定义的大量多样的物质。尽管有明确的科学证据表明其对人类健康的负面影响，但对吸入剂的滥用仍然是全球医学问题。预测是否会滥用吸入剂并为吸入滥用的治疗方法开发需要适当的实验程序，以模拟成瘾过程的不同方面。该建议将研究在这些程序中评估两种原型吸入剂的滥用相关作用的基本行为程序：甲苯和一氧化二氮。我们的第一个目标是检查这些吸入剂的急性奖励效果。两组16个C57BL6/J小鼠将用慢性双极电极植入其内侧前脑束中。然后，将训练小鼠在空气暴露条件下响应电刺激。建立基线后，一半的小鼠将暴露于甲苯或一氧化二氮的增加或降低，同时允许对ICS做出响应。通过检查ICSS频率响应曲线的变化，响应的渐进比率时间表以及最后的基线阈值移位，可以评估ICS奖励效应的变化。从机械上讲，我们将通过对选择性剂进行预处理以阻止促进性的预处理来探讨GABA和NMDA介导的ICS促进。与虐待相关的依赖性和戒断效应，例如Anhedonia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退出是否会产生Anhedonic效应，如ICSS阈值的变化和类似焦虑的效果所衡量的那样，通过高架的性能以及迷宫和轻/深色盒子的探索来衡量。三组为16个C57BL6/J小鼠将植入慢性双极ICSS电极，并经过训练，以响应ICS直至稳定。然后将小鼠暴露于10天的24小时/天暴露于甲苯或一氧化二氮，其浓度低于产生明显的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。在随后的撤回期间，ICSS阈值将在停用吸入式暴露后的4、8、24和48小时确定。每次ICS会议之后，还将检查高架的迷宫和轻/深色盒性能。最后，我们将检查吸入剂产生的大脑奖励电路的持续变化，这被认为是复发的主要因素，由于长期暴露，将检查在长期暴露研究中使用的相同小鼠ICSS性能的长期变化。 ICSS测试将在空气暴露条件下每天进行，并将其与在慢性吸入暴露之前以及空气控制组之前产生的ICSS频率响应曲线进行比较。我们认为，该项目对人类成瘾过程的多个组成部分进行了建模，可以更好地了解吸入剂的滥用相关影响，并生产适合检查机制的模型和吸入滥用的潜在治疗药物。