Mechanisms of Amphetamine Withdrawal and Recovery

描述(申请人提供)：这项研究的长期目标是确定有助于从精神运动兴奋剂使用中恢复的因素，并针对这些药物对健康的负面影响开发预防和治疗方法。当给大鼠全身注射中等剂量的苯丙胺(AMPH)时，动物在给药后的头几个小时内过度活跃，在给药后19-21小时内活动不足，在给药后25-30小时内轻度过度活动。这些活动的变化反映了Amph产生即刻精神运动刺激状态、短暂性戒断和代偿恢复的能力。短暂性戒断和恢复似乎是一系列综合反应，反映了动物在接受药物后维持健康的能力。拟议研究的具体目的是评估有关可能产生暂时性戒断和代偿性恢复的机制的假设。在一系列研究中，我们将观察选择性刺激多巴胺能系统中DA受体亚型或主要终末区域是否足以产生指示短暂戒断和代偿性恢复的运动活动的变化。不同组的大鼠将接受不同剂量的d1受体激动剂SKF 81297或d2受体激动剂奎匹罗；或者向伏隔核或背侧纹状体微量注射Amph。为了评估这些治疗对活动模式的影响，受试者将被安置在单独的站点，在那里可以持续监测活动。将使用一种灵敏的方法来确定药物引起的活性变化，并将使用一种负担得起的、信息丰富的新方法来量化活动。

DESCRIPTION (provided by applicant): The long-term objectives of this research are to identify factors that contribute to recovery from psychomotor stimulant use, and to develop preventions and treatments for the negative effects on health that these drugs have. When a moderate dose of amphetamine (AMPH) is administered systemically to a rat, the animal is excessively active during the first several hours after administration, it is hypoactive during hours 19-21 post-administration, and it is mildly hyperactive during hours 25-30 post-administration. These changes in activity reflect the ability of AMPH to produce an immediate psychomotor stimulant state, a transitory withdrawal, and a compensatory recovery. Transitory withdrawal and recovery appear to be an integrated series of responses that reflect the animal's capacity to maintain health in the face of drug receipt. The specific aim of the proposed studies is to assess hypotheses regarding mechanisms that might produce transitory withdrawal and compensatory recovery. In a series of studies we will see if selective stimulation of DA receptor subtypes or of major terminal areas in the dopaminergic systems are sufficient to produce changes in locomotor activity indicative of transitory withdrawal and compensatory recovery. Different groups of rats will receive different doses of SKF 81297, a D1 receptor agonist, or of quinpirole, a D2 receptor agonist; or they will receive microinjections of AMPH into the nucleus accumbens or the dorsal striatum. In order to evaluate the effects of these treatments on patterns of activity, subjects will be housed in individual stations where activity can be continuously monitored. A sensitive method will be used to identify drug-induced changes in activity against the background of activity entrained by the light-dark cycle, and an affordable and informative new method will be used for quantifying activity.