ENDURING CHANGES IN BRAIN PRODUCED BY STIMULANTS

兴奋剂引起的大脑持久变化

基本信息

批准号：
3074714
负责人：
Terry E. Robinson
金额：
$ 5.02万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-06-01 至 1989-05-31
项目状态：
已结题

项目摘要

It is well established that the repeated administration of stimulant drugs (e.g. amphetamine) results in a progressively enhanced behavioral response to subsequent injections. This phenomenon of 'reverse tolerance', or sensitization, has generated considerable interest because it is thought to provide an animal analogue of amphetamine (AMPH) psychosis in humans. However, a single injection of AMPH may also produce a long-lasting change in brain activity. In preliminary studies using AMPH-induced rotational behavior as an index of mesostriatal dopamine (DA) activity we found that a single injection of a low dose (1.25 mg/kg) of AMPH greatly enhanced the rotational behavior produced by a second injection of AMPH given 3-4 weeks later in intact female, ovariectomized female and castrated male rats. Intact males did not show as robust a change. This behavioral sensitization may be due to changes in DA release, since it is accompanied by a long-lasting enhancement in AMPH-stimulated endogenous DA release from striatal tissue in vitro. The studies proposed here are disigned to: (1) further characterize the phenomenon of long-term changes in rotational behavior produced by a single or repeated injections of AMPH: (2) examine the role of gonadal steroid hormones in modulating this form of neural plasticity; (3) further explore the possibility that long-lasting changes in DA release from terminals in a variety of brain regions are involved in the development of behavioral sensitization; (4) determine whether similar long-lasting changes in brain activity are produced by other stimulant drugs; and (5) determine whether a single injection of AMPH will produce comparable changes in other behaviors thought to be mediated by brain DA systems. We believe the proposed studies integrating both in vivo and in vitro approaches will increase our understanding of the basic neurobiological mechanisms involved in neuroplasticity. The studies are of clinical interest since they may provide some insight as to the neurochemical changes underlying AMPH psychosis. Lastly, the fact that the single administration of psychostimulant drugs may result in long-term physiological alterations should be of obvious practical concern in psychotherapeutics.

众所周知，重复服用兴奋剂药物（例如安非他明）导致行为反应逐渐增强到后续的注射。这种“反向耐受”现象，或者敏化，引起了相当大的兴趣，因为它被认为提供人类安非他明（AMPH）精神病的动物类似物。然而，单次注射 AMPH 也可能产生持久的变化在大脑活动中。在使用 AMPH 诱导旋转的初步研究中行为作为中纹状体多巴胺（DA）活性的指标，我们发现单次注射低剂量（1.25 mg/kg）的 AMPH 大大增强了 3-4 周内第二次注射 AMPH 产生的旋转行为随后在完整的雌性、卵巢切除的雌性和阉割的雄性大鼠中进行实验。完整的雄性并没有表现出如此强烈的变化。这种行为致敏可能是由于 DA 释放的变化造成的，因为它伴随着通过持久增强 AMPH 刺激的内源性 DA 释放体外纹状体组织。这里提出的研究旨在：（1）进一步表征旋转的长期变化现象单次或重复注射 AMPH 产生的行为：(2) 检查性腺类固醇激素在调节这种形式的神经元中的作用可塑性; (3)进一步探讨持久变化的可能性不同脑区末端的 DA 释放参与行为敏感性的发展； (4)判断是否相似其他兴奋剂会产生大脑活动的持久变化毒品； (5) 确定单次注射 AMPH 是否会产生被认为由大脑 DA 介导的其他行为的类似变化系统。我们相信所提出的研究整合了体内和体内体外方法将增加我们对基本原理的理解涉及神经可塑性的神经生物学机制。这些研究是临床兴趣，因为它们可能提供一些关于 AMPH 精神病背后的神经化学变化。最后，事实是单独服用精神兴奋药物可能会导致长期生理变化应该引起明显的实际关注心理治疗。