CHRONIC DRUGS: CNS BIOCHEMISTRY AND BEHAVIOR

申请者摘要：安非他命、可卡因和类似的兴奋剂会导致 与剂量和慢性相关的从全身性唤醒到 刻板印象，以及这种转变背后的机制可能 对药物滥用的重要影响。最新的应用 微透析方法学提供了更直接的机会 评估神经系统/行为关系，以及使用 这种方法证实了这些刺激剂对 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 显示出明显的解离表达之间的特异性 刺激诱导的行为和尾状核和尾状核的数量方面 伏隔核多巴胺能反应。因此，我们假设 从移动到刻板印象的行为转变不能用 单单是多巴胺的数量变化，而是涉及 多巴胺与其他递质的相互作用，包括5-羟色胺和 去甲肾上腺素存在于几个前脑结构中。此外，在此基础上， 在我们最近的结果中，我们假设(1) 脉冲流水平与邻苯二酚-O-甲基儿茶酚的利用度 尾状核和伏隔核之间的转移酶有助于优先 伏隔对多巴胺摄取阻滞剂的反应而不是多巴胺 释放剂；(2)苯丙胺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)可卡因对细胞外多巴胺的增强作用并不严格。 依赖于摄取阻断。为了检验这些假设，我们首先 扩大我们对苯丙胺和其他药物影响的描述 对局部多巴胺有不同作用机制的兴奋剂， 血清素和去甲肾上腺素。将使用各种操作来 研究多巴胺神经元冲动流的作用， 儿茶酚-O-甲基转移酶活性和胞质动态 和多巴胺的囊泡池来刺激多巴胺的释放。 尾液透析液中乙酰胆碱的测定将提供一种方法 突触后受体功能评估5-羟色胺的关系 和多巴胺受体对行为反应成分的激活。 突触神经递质动力学伴随的直接评价 行为分析将进一步阐明刺激剂-神经递质 互动。

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.