Mechanisms of Amphetamine Withdrawal and Recovery

描述（由申请人提供）：本研究的长期目标是确定有助于从精神兴奋剂使用中恢复的因素，并为这些药物对健康的负面影响制定预防和治疗措施。当对大鼠全身给予中等剂量的安非他明（AMPH）时，动物在给药后的最初几个小时内过度活跃，在给药后19-21小时内活动减退，在给药后25-30小时内轻度过度活跃。这些活动的变化反映了AMPH产生即时精神兴奋状态、短暂戒断和代偿性恢复的能力。暂时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保持健康的能力。拟议研究的具体目的是评估关于可能产生暂时戒断和补偿性恢复的机制的假设。在一系列的研究中，我们将看到是否选择性刺激多巴胺受体亚型或多巴胺能系统中的主要终末区足以产生自发活动的变化，表明短暂的退缩和代偿性恢复。不同组的大鼠将接受不同剂量的SKF 81297（一种D1受体激动剂）或quinpirole（一种D2受体激动剂）;或者它们将接受AMPH微量注射到延髓核或背侧纹状体。为了评价这些治疗对活动模式的影响，受试者将被安置在可以连续监测活动的单独工作站中。将使用灵敏的方法来识别药物诱导的活性变化，以明-暗循环所携带的活性为背景，并将使用负担得起的和信息丰富的新方法来量化活性。

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.