BEHAVIORAL PHARMACOLOGY OF ACUTE AND CHRONIC AMPHETAMINE

描述：(申请人摘要) 兴奋剂对人类的成瘾和心理影响是最大的 通常与一种重复的“狂欢”暴露模式有关，在这种模式之前 逐步升级的药物丢失(ED)。要模拟这些 在这种情况下，我们将大鼠暴露在多种兴奋剂狂欢中，在此之前 相对长期、间歇性或ED。安非他明治疗的大鼠 (安非他明)、甲基苯丙胺或可卡因，逐渐形成了一种独特的行为 由连续刻板印象的减少组成的概况 分量，运动量的显著增加，以及 行走中的质变。此外，在多次高剂量下， AMPH暴饮暴食，尾壳核细胞外多巴胺(DA)反应，但 不是伏隔核的DA反应，发展出了一种深刻的 对药物引起的细胞外增加的耐受性/快速反应 发射机。5-羟色胺也得到了类似的结果，而 海马区和额叶皮质去甲肾上腺素反应增强。我们的 拟议的研究旨在进一步检查神经化学和 与ED/Binges相关的行为过程。我们将使用微透析 进一步说明区域发展议程反应之间的关系 移位和紧急行为特征(EBP)的表达。更低的位置 AMPH剂量以及其他兴奋剂将被用来确定 这种关系的普遍性以及行为和行为的持久性 神经化学变化。可能的分子机制 区域发展议程反应转移，以及其他发展议程系统在 还将检查行为反应。行为(惊吓和噪音 范例)和神经内分泌指标(CRF、皮质酮、ACTH、 催乳素)将被用来检验我们的假设，即EBP反映了 高度兴奋的或有压力的状态。更多的研究旨在进一步 评估去甲肾上腺素、5-羟色胺和谷氨酸的作用 EBP中的系统。阐明潜在的神经生物学过程 与ED/BING治疗相关的行为变化可能有 对了解兴奋剂成瘾和复发的影响，以及 对大剂量精神毒性效应的持续性超敏反应 兴奋剂滥用。

DESCRIPTION: (Applicant's Abstract) The addictive and psychogenic effects of stimulants in humans are most commonly associated with a pattern of repeated "binge" exposures preceded by progressively escalating loses (ED) of the drug. To simulate these conditions, we exposed rats to multiple stimulant binges, preceded by relatively long-term, intermittent or ED. Rats treated with amphetamine (AMPH), methamphetamine, or cocaine, gradually developed a unique behavioral profile which consisted of a decrease in the continuous stereotypy component, a pronounced increase in the magnitude of locomotion, and a qualitative change in the ambulation. Furthermore, with multiple high dose AMPH binges, the caudate-putamen extracellular dopamine (DA) response, but not the nucleus accumbens DA response, developed a profound tolerance/tachyphylaxis to the drug-induced increase in extracellular transmitter. Similar results were obtained with serotonin, whereas the hippocampus and frontal cortex norepinephrine responses were increased. Our proposed research is designed to further examine the neurochemical and behavioral processes associated with ED/Binges. We will use microdialysis to further characterize the relationship between the regional DA response shift and the expression of the emergent behavioral profile (EBP). Lower AMPH doses as well as other stimulants will be used to determine the generality of this relationship and the persistence of the behavioral and neurochemical changes. Possible molecular mechanisms underlying the regional DA response shift, and the role of other DA systems in the behavioral response will also be examined. Behavioral (startle and noise paradigms) and neuroendocrine measures (CRF, corticosterone, ACTH, prolactin) will be used to test our hypothesis that the EBP reflects a highly aroused or stressed state. Additional studies are aimed at further assessing the roles of noradrenergic, serotonergic, and glutamatergic systems in the EBP. Elucidation of the neurobiological processes underlying the behavioral changes associated with the ED/Binge treatment may have implications for understanding stimulant addiction and relapse, and the persistent hypersensitivity to the psychotoxic effects of high dose stimulant abuse.