ORAL BENZODIAZEPINE SELF ADMINISTRATION

申请人摘要： 新的短效苯二氮卓类和部分激动剂的介绍 导致人们越来越感兴趣的加强效果的 苯二氮卓类 然而，对影响因素的严格研究 苯二氮卓类药物的增强作用由于缺乏 成功地将这些药物确立为口服给药的药物， 实验室动物 我们已经制定了程序， 给恒河猴注射苯二氮卓类药物。 苯二 幼稚的猴子拒绝这些药物溶液，而更喜欢水。 因此 培训或采购程序是必要的。 随着咪达唑仑的消退 使用了一种程序，其中将增加量的药物加入到 乙醇溶液（已经用作增溶剂）。 在第二 相乙醇溶液逐渐减少到零，仅留下 咪唑安定 在完成该程序后，米多安定起到了 - 好的 使用地西泮的程序很简单， 代替咪达唑仑。 最近我们成功地用 三唑仑和阿普唑仑代替咪达唑仑。 现在我们有四个 苯二氮卓类药物（咪达唑仑、地西泮、三唑仑和 阿普唑仑）。 这项补助金的目的是扩大对 口服苯二氮卓类药物的开发和维持 恒河猴的排泄物。 一个重要的特点是， 具有不同药代动力学和药效学特征的苯二氮卓类药物 将检查是否有不同的强化效果。 既往用药史在确定是否获得 加强效果将被审查，以及程序， 通过用一种苯并二氮杂卓取代 另 将仔细检查剂量的基本变量， 范围广泛的价值观和跨苯二氮卓类。 的影响 苯二氮卓受体拮抗剂氟马西尼将在以下方面进行检查： 苯二氮卓类药物的变化增强了反应。 允许a的程序 在不同液体之间的选择是一种严格且通常快速的方法， 确定相对强化效果。 在本申请中， 程序将用于研究不同浓度的 同样的药。 此外，将使用累进比率程序来测量 不同剂量的强化效果。 两个程序的结果 将被比较。 将综合这些研究的结果 与我们在其他药物研究中获得的结果相比， 药理学类。 这项研究的结果将增加 根据我们对控制收购的因素的了解， 维持苯二氮卓类强化行为。

APPLICANT'S ABSTRACT: The introduction of new short-acting benzodiazepines and partial agonists has led to an increased interest in the reinforcing effects of the benzodiazepines. However, rigorous study of factors influencing the reinforcing effects of benzodiazepines has been limited due to the lack of success in establishing these drugs as orally delivered reinforcers for laboratory animals. We have developed procedures to establish orally delivered benzodiazepines as reinforcers for rhesus monkeys. Benzodiazepine naive monkeys reject these drug solutions and prefer water. Thus, a training or acquisition procedure is necessary. With midazolam a fading procedure was used whereby increasing amounts of drug were added to an ethanol solution (that was already serving as a reinforcer). In the second phase ethanol solution was gradually decreased to zero, leaving only the midazolam. Upon completion of this procedure midozalam functioned as a reinforcer. The procedure used with diazepam was simple, diazepam was substituted for midazolam. Recently we have successfully substituted triazolam and alprazolam for midazolam. At this point we have four benzodiazepines serving as reinforcers (midazolam, diazepam, triazolam & alprazolam). The aim of this grant is to expand the study of the development and maintenance of orally delivered benzodiazepines as reinforcers for rhesus monkeys. An important feature is that benzodiazepines with different pharmacokinetic and pharmacodynamics profiles will be examined to see if there are differences in reinforcing effects. The importance of prior drug history in determining acquisition of reinforcing effects will be examined as well as the procedure of establishing reinforcing effects by substituting one benzodiazepine for another. The fundamental variable of dose will be carefully examined across a broad range of values and across benzodiazepined. The effects of the benzodiazepine receptor antagonist, flumazenil, will be examined in terms of changes in benzodiazepine reinforced responding. Procedures that permit a choice between different liquids are a rigorous and often rapid method for determining relative reinforcing effects. In the present application such procedures will be used to study choices between different concentrations of the same drug. Also, a progressive ratio procedure will be used to measure reinforcing effects of different doses. The results of the two procedures will be compared. Results obtained from these studies will be integrated with the results we have obtained in studies of drugs from other pharmacological classes. The results of this research will add substantially to our knowledge of factors controlling the acquisition and maintenance of benzodiazepine reinforced behavior.