NEURAL MECHANISMS OF DRUG SEEKING BEHAVIOR

描述：（申请人摘要） 对动物觅药行为的测量提供了可用于 筛选治疗人类药物渴求和复发的潜在方法， 研究相关的神经机制 这些措施包括： 当药物不再可用时响应药物（即，灭绝）和 通过给药或介绍恢复应答 与毒品有关的线索 拟议研究的目的是 研究单胺（MA）系统在可卡因寻求行为中的作用， 灭绝/恢复模式。 训练动物用杠杆挤压食物 将接受自我管理可卡因的训练， 给予盐水。 在响应建立后，他们将 每天进行14次3小时的训练，然后进行最后12小时的“狂欢” 上网时段 后来，吸毒行为，以及MA溢出 杏仁核和杏仁核，将在3个测试阶段进行评估：第1阶段 将评估消退期间的操作性反应;第2阶段将评估 通过呈现可卡因相关线索恢复反应; 第三阶段将评估可卡因后反应的恢复情况。 注射 第二天，将检查觅食行为， 确定以前观察到的变化是否是特定于药物寻求。 第一个实验将研究 可卡因戒断过程中的觅药行为和MA溢出 在最后一次给药后6小时、30小时、7天或28天， 自我管理会议。 其次，慢性治疗的效果， 去甲丙咪嗪（DEMETHYMIMPRAMINE，MA再摄取抑制剂， 疗效，对药物寻求行为和MA溢出将进行研究。 马 还将在死后测定受体密度。 它是假设 可卡因戒断将导致寻求毒品的时间依赖性增加 与MA系统中的神经化学变化相关的行为，以及 在戒断期间进行适当的治疗会减少寻求药物的行为， 并逆转神经化学变化 表征时间依赖性 药物寻求行为和MA系统的变化将提供更好的 了解可卡因戒断和复发，并可能提供洞察力 寻找毒品行为的神经机制 该信息 对于开发可卡因渴望的药物治疗至关重要， 复发 最后一个实验将研究假设， 多巴胺D3-偏好激动剂7-OH-DPAT减弱药物寻求行为。 如果得到证实，这一发现将提出一种新的药物治疗方法。 可卡因依赖症的治疗策略。

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.