ENDURING CHANGES IN BRAIN PRODUCED BY STIMULANTS

兴奋剂引起的大脑持久变化

• 批准号: 3074712
• 负责人: Terry E. Robinson
• 金额: $ 5.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/3074712
• 关键词: amphetamines; behavior test; central nervous system stimulants; chordate locomotion; corpus striatum; dihydrotestosterone; dopamine; dosage; drug hypersensitivity; estrogens; experimental brain lesion; gender difference; high performance liquid chromatography; hypothalamus; male castration; neural plasticity; neuroendocrine system; neurotransmitter biosynthesis; organic brain syndrome; ovariectomy; pharmacokinetics; psychopharmacology; sex hormones; testosterone

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，刺激性药物的重复给药 （例如，苯丙胺）导致行为反应逐渐增强 随后注射。 这种“反向宽容”的现象，或 敏化，引起了极大的兴趣，因为它被认为是 提供人类中苯丙胺（AMPH）精神病的动物类似物。 但是，单一注入AMPH也可能会产生持久的变化 在大脑活动中。 在使用AMPH诱导的旋转的初步研究中 行为作为介叶胺多巴胺（DA）活性的指数，我们发现A 单剂量的低剂量（1.25 mg/kg）的Amph大大增强了 第二次注射AMPH产生的旋转行为给定3-4周 后来以完整的女性，卵巢切除的雌性和cast割的雄性大鼠。 完整的男性并没有表现出强大的变化。 这种行为 敏化可能是由于DA释放的变化，因为它伴随 通过在Amph刺激的内源性DA释放中持续增强 体外纹状体组织。 此处提出的研究被解雇为：（1） 进一步表征了旋转长期变化的现象 通过单一或重复注射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中的作用 可塑性; （3）进一步探索持久变化的可能性 在从终端释放的各种大脑区域的DA中涉及 行为敏化的发展； （4）确定是否相似 大脑活动的长期变化是由其他兴奋剂产生的 毒品； （5）确定单一注射AMPH是否会产生 其他被认为是由大脑DA介导的其他行为的可比变化 系统。 我们认为，拟议的研究既整合体内和体内 体外方法将增加我们对基本的理解 涉及神经塑性的神经生物学机制。 研究是 临床兴趣，因为它们可能会对 神经化学的变化是AMPH精神病。 最后，事实是 精神刺激药物的单一给药可能会导致长期 生理改变应该显而易见 心理治疗学。