CHRONIC DRUGS: CNS BIOCHEMISTRY AND BEHAVIOR

申请人摘要：安非他明、可卡因和类似兴奋剂会引起 剂量和慢性相关的从全身性觉醒到 刻板印象，这种转变的机制可能有 对药物滥用的重要影响。 的应用进展 微透析方法提供了更直接地 评估神经系统/行为关系，以及使用 这种方法证实了这些兴奋剂对 多巴胺系统 然而，我们的伴随行为/生物化学 使用定制设计的微透析方法的表征具有 揭示了一个明确的分离之间的表达特异性 刺激诱导的行为和定量方面的尾状核， 多巴胺能反应。 我曾以为， 从运动到刻板的行为转变不能用 多巴胺本身的数量变化，而是涉及到 多巴胺与其他递质的相互作用，包括血清素和 去甲肾上腺素在几个前脑结构。 此外，根据 根据我们最近的研究结果，我们假设（1） 脉冲流的水平和儿茶酚-O-甲基的可用性 尾状核和尾状核之间的转移酶有助于优先 多巴胺摄取阻滞剂对多巴胺的反应 释放剂;（2）安非他明与摄取载体的相互作用， 细胞质多巴胺池的大小限制了多巴胺的释放; (3)可卡因诱导的细胞外多巴胺的增强并不严格 依赖于摄取阻断。 为了验证这些假设，我们将首先 扩大我们对安非他明和其他毒品的影响的描述， 对局部多巴胺具有不同作用机制的兴奋剂， 血清素和去甲肾上腺素 各种各样的操作将被用来 检查多巴胺神经冲动流的贡献， 儿茶酚-O-甲基转移酶活性，以及细胞质的动态变化。 以及多巴胺的囊泡池到刺激物诱导的多巴胺释放。 测量尾状核透析液中的乙酰胆碱将提供一种测量 突触后受体功能的研究，以评估血清素 和多巴胺受体激活的行为反应的组成部分。 突触神经递质动力学的直接评价 行为分析将进一步阐明兴奋剂神经递质 交互.

APPLICANT'S ABSTRACT: Amphetamine, cocaine, and like stimulants induce a dose- and chronicity-related transition from generalized arousal to stereotypies, and the mechanisms underlying this transition may have important implications for drug abuse. The recent application of microdialysis methodology has provided the opportunity to more directly evaluate neuronal-system/behavior relationships, and data obtained using this methodology confirm the profound effects of these stimulants on dopamine systems. However, our concomitant behavior/biochemistry characterizations using custom-designed microdialysis methodology have revealed a clear dissociation between the expression of specific stimulant-induced behaviors and the quantitative aspects of the caudate and accumbens dopaminergic response. Thus we have hypothesized that the behavioral transition from locomotion to stereotypy cannot be explained by the quantitative changes in dopamine alone, but rather involves the interaction of dopamine with other transmitters, including serotonin and norepinephrine in several forebrain structures. In addition, on the basis of our more recent results, we have hypothesized that (1) differences in the levels of impulse flow and the availability of catechol-O-methyl transferase between caudate and accumbens contribute to a preferential response of accumbens to dopamine uptake blockers but not dopamine releasers; (2) interaction of amphetamine with the uptake carrier and not the size of the cytoplasmic dopamine pool limits the release of dopamine; (3) cocaine-induced enhancement of extracellular dopamine is not strictly dependent on uptake blockade. To test these hypotheses, we will first extend our characterization of the effects of amphetamine and other stimulants with differing mechanisms of action on regional dopamine, serotonin and norepinephrine. A variety of manipulations will be used to examine the contribution of dopamine neuronal impulse flow, catechol-O-methyl transferase activity, and the dynamics of the cytoplasmic and vesicular pools of dopamine to stimulant-induced dopamine release. Measurement of acetylcholine in caudate dialysates will provide a measure of post-synaptic receptor function to assess the relationship of serotonin and dopamine receptor activation to components of the behavioral response. The direct evaluation of synaptic neurotransmitter dynamics concomitant with behavioral analysis will further elucidate stimulant-neurotransmitter interactions.