NEURAL MECHANISMS OF DRUG SEEKING BEHAVIOR

描述：(申请人摘要) 动物寻药行为的测量提供了可以使用的模型 筛选人类药物渴求和复发的潜在治疗方法，并 研究涉及的神经机制。这些措施包括可操作性 在药物不再可用时对药物作出反应(即，灭绝)和 恢复借给药或呈交而作出回应 与毒品有关的线索。拟议研究的目标是 研究单胺(MA)系统在寻找可卡因行为中的作用 灭绝/复活模式。被训练用杠杆压榨获取食物的动物 将接受自我管理可卡因的培训，或将接受枷锁 注射生理盐水。在建立响应后，他们将 每天接受14次3小时的培训，然后是最后12小时的“狂欢” 会议。后来，寻毒行为以及MA泛滥在 伏隔核和杏仁核将在3个测试阶段进行评估：阶段1 将评估生物在灭绝期间的反应；第二阶段将评估 通过提供与可卡因有关的线索恢复反应； 第三阶段将评估可卡因后反应的恢复 注射。第二天，将对觅食行为进行检查 确定以前观察到的变化是否特定于药物寻找。 第一个实验将检验在变化中的关系 可卡因戒断过程中的寻药行为与MA溢出 最后一次实验后6小时、30小时、7天或28天的动物分组测试 自我管理会话。其次，慢性用药的效果 去甲基米帕明(DMI)，一种具有一定抗瘾作用的MA再摄取抑制剂 对药物寻找行为和MA溢出的疗效进行调查。体量 受体密度也将在死后进行检测。据推测， 戒除可卡因会使寻求毒品的人数呈时间依赖性增加 与MA系统中的神经化学变化相关的行为，以及 戒断期间的DMI治疗将减轻寻求毒品的行为 并逆转神经化学变化。表征随时间变化的特性 寻求毒品行为和MA制度的改变将提供更好的 了解可卡因的戒断和复发，并可能提供洞察力 寻找毒品行为的神经机制。此信息是 对于开发药物治疗可卡因的渴求和 旧病复发。最后的实验将调查这样一种假设 多巴胺D3--偏爱激动剂7-OH-DPAT可减弱寻求药物的行为。 如果得到证实，这一发现将提出一种新的药物治疗方法。 可卡因依赖战略。

DESCRIPTION: (Applicant's Abstract) Measures of drug-seeking behavior in animals provide models that can be used to screen potential treatments for drug craving and relapse in humans and to study the neural mechanisms involved. These measures include operant responding for drug when it is no longer available (i.e., extinction) and reinstatement of responding either by administration of drug or presentation of drug-associated cues. The objective of the proposed research is to examine the role of monoamine (MA) systems in cocaine-seeking behavior using the extinction/reinstatement model. Animals trained to lever press for food will be trained to self-administer cocaine or will receive yoked administration of saline. After responding has been established, they will be given 14 daily 3-hr training sessions, followed by a final 12-hr "binge" session. Later, drug-seeking behavior, as well as MA overflow in the nucleus accumbens and amygdala, will be assessed in 3 test phases: phase 1 will assess operant responding during extinction; phase 2 will assess reinstatement of responding by presentation of cocaine-associated cues; phase 3 will assess reinstatement of responding following a cocaine injection. The following day, food-seeking behavior will be examined to determine whether changes observed previously are specific to drug-seeking. The first experiment will examine the relationship between changes in drug-seeking behavior and MA overflow during cocaine withdrawal in separate groups of animals tested 6 hr, 30 hr, 7 or 28 days after the last self-administration session. Next, the effect of chronic treatment with desmethylimipramine (DMI), a MA reuptake inhibitor with some anti-craving efficacy, on drug-seeking behavior and MA overflow will be investigated. MA receptor density will also be assayed post-mortem. It is hypothesized that cocaine withdrawal will produce a time-dependent increase in drug-seeking behavior that will correlate with neurochemical changes in MA systems, and that DMI treatment during withdrawal will attenuate drug-seeking behavior and reverse the neurochemical changes. Characterizing time-dependent changes in drug-seeking behavior and MA systems will provide a better understanding of cocaine withdrawal and relapse, and may provide insight into the neural mechanisms of drug-seeking behavior. This information is crucial for developing pharmacologic treatments for cocaine craving and relapse. The last experiments will investigate the hypothesis that the dopamine D3-- preferring agonist 7-OH-DPAT attenuates drug-seeking behavior. If confirmed, the findings would suggest a new pharmacologic treatment strategy for cocaine dependence.