BEHAVIORAL CHARACTERIZATION OF ACUTE&CHRONIC AMPHETAMINE

甲基苯丙胺的滥用在过去十年中显著增加，相对纯净、高效的毒品形式的可获得性导致了更长期、高剂量的暴露模式。越来越多的证据表明，滥用甲基苯丙胺可能会导致深刻的神经化学和神经精神变化，纹状体多巴胺传递的变化可能与其中许多影响有关。然而，目前尚不清楚这些变化是否反映了神经退化或适应性调整，也不清楚停药后是否发生了功能恢复。这些信息是合理开发有效的治疗干预措施的关键前提。这项拟议的研究将使用一种新开发的甲基苯丙胺治疗范式，该范式在大鼠身上密切模拟与高剂量甲基苯丙胺滥用相关的药物暴露条件，以表征与纹状体多巴胺神经元传递相关的广泛神经化学和行为指标的时间变化。这些特定的研究旨在验证我们的假设：(1)在没有多巴胺神经元变性的情况下，每天重复多次服用甲基苯丙胺将产生严重的神经化学(纹状体多巴胺神经末梢标记物)和行为(自发活动、行为组织和短期记忆)损害；(2)随着时间的推移，多巴胺传递的变化(包括多巴胺转运体和囊泡单胺转运体的测量，以及细胞外多巴胺)和相关行为缺陷将完全恢复；(3)在甲基苯丙胺治疗的后期，与兴奋剂滥用者发展成偏执型精神病有关的一系列行为(过度觉醒、攻击性增强和对应激的反应性)将逐渐出现，与相对尾壳核和伏隔核多巴胺反应的变化相对应；以及(4)对急性甲基苯丙胺刺激的改变的行为效应和多巴胺效应在停止慢性治疗后将随着时间的推移逐渐恢复。这些研究的结果应该能更深入地了解与滥用甲基苯丙胺的常见模式相关的行为和神经化学后果的机制和过程。

Methamphetamine abuse has significantly increased over the past decade and the availability of relatively pure, high potency forms of the drug has led to more chronic, high dose exposure patterns. Converging evidence suggests that profound neurochemical and neuropsychiatric changes can result from methamphetamine abuse and that alterations in striatal dopamine transmission may be implicated in many of these effects. However, it is unclear whether these changes reflect neurodegeneration or adaptational adjustments, nor if functional recovery occurs after discontinuation of drug. Such information is a critical prerequisite to the rational development of effective therapeutic interventions. The proposed research will use a newly developed methamphetamine treatment paradigm that closely simulates, in rats, the drug exposure conditions associated with a high dose, maintenance pattern of methamphetamine abuse, in order to characterize the temporal changes of a broad spectrum of neurochemical and behavioral indices associated with striatal dopamine neuronal transmission. The specific studies are designed to test our hypotheses that: (1) repeated multiple daily administration of methamphetamine will produce profound neurochemical (striatal dopamine nerve terminal markers) and behavioral (spontaneous activity, behavioral organization, and short-term memory) impairments in the absence of dopamine neuronal degeneration; (2) the changes in dopamine transmission (including measures of the dopamine transporter and the vesicular monoamine transporter, as well as extracellular dopamine) and related behavioral deficits will exhibit complete recovery over time; (3) during the late stages of methamphetamine treatment, a spectrum of behaviors associated with the development of paranoid psychosis in stimulant abusers (hyperarousal, increased aggressivity and responsiveness to stress) will gradually emerge, corresponding to a shift in the relative caudate-putamen and nucleus accumbens dopamine responses; and, (4) both the altered behavioral and dopamine effects in response to acute methamphetamine challenge will exhibit gradual recovery over time after discontinuation of chronic treatment. The results of these studies should provide greater insight into the mechanisms and processes contributing to the behavioral and neurochemical consequences associated with a common pattern of methamphetamine abuse.