Acute and Chronic Effects of Inhalants in ICSS

描述（由申请人提供）：吸入剂是一大类不同的物质，按给药途径定义松散。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，但滥用吸入剂仍然是一个世界性的医疗问题。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。本提案将研究在这些程序中评估两种原型吸入剂：甲苯和氧化亚氮的滥用相关影响的基本行为程序。我们的第一个目标将是检查这些吸入剂的急性奖励效应。将两组16只C57BL6/J小鼠内侧前脑束内植入慢性双极电极。然后，老鼠将被训练在空气暴露条件下对电刺激做出反应。在确定基线后，一半小鼠将暴露于浓度增加或减少的甲苯或一氧化二氮中，同时允许对ICSS作出反应。ICSS奖励效果的变化将通过检查ICSS频率响应曲线的变化、响应的递进比率时间表和最后的基线阈值变化来评估。在机制上，我们将探讨GABA和NMDA介导的ICSS的促进作用，通过预处理选择性药物阻断促进作用。与滥用相关的依赖和戒断效应，如快感缺乏和焦虑，是成瘾的关键组成部分。因此，我们将通过ICSS阈值的变化来检测慢性吸入剂暴露的戒断是否会产生快感缺乏效应，以及通过在高难度迷宫和光/暗盒探索中的表现来检测焦虑样效应。将三组16只C57BL6/J小鼠植入慢性双极ICSS电极，并训练其对ICSS的反应，直至稳定。然后将小鼠暴露在浓度略低于产生明显急性行为影响的甲苯或一氧化二氮中10天，每天24小时。第三组作为对照，只暴露在相同条件下的空气中。在随后的停药期间，ICSS阈值将在停止吸入剂暴露后4、8、24和48小时确定。在每次ICSS会议结束后，还将检查高架加迷宫和光/暗盒的表现。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，在慢性暴露研究中使用的相同小鼠将被检查慢性暴露导致的ICSS表现的长期变化。将在空气暴露条件下每天进行ICSS试验，并与慢性吸入剂暴露前产生的ICSS频率响应曲线以及空气控制组进行比较。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。

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.