NEUROCHEMICAL PLASTICITY AND DRUG RESPONSES--AMPHETAMINE

这项研究建议的主要论点是中枢神经 构成吸毒行为基础的制度变化涉及长期 适应现象，包括系统内适应和系统间适应 改编。因此，对药物影响的分析不仅包括 延伸到药物的主要作用之外将在 进一步加深了我们对药物滥用的细胞方面的理解。 在这个框架内，我们建议彻底分析以下因素的影响 苯丙胺，一种高度滥用的精神运动兴奋剂，对 包括基底节和相关神经回路的神经化学 丘脑皮质结构。该电路潜在地能够 对精神运动行为的强烈影响。因为主要的行动是 大脑中的苯丙胺是神经递质多巴胺的释放 假设在本电路中的系统内适应将涉及 直接的多巴胺神经元，而系统间的适应 延伸到多巴胺所在的神经化学回路。这个 目前的实验利用体内微透析技术来 在行为正常的大鼠中，监测其胞外浓度 神经递质多巴胺和乙酰胆碱在其中的几个点 首先，我们建议记录苯丙胺对 纹状体多巴胺/乙酰胆碱的动态变化。我们将把我们的分析扩展到 包括苯丙胺对纹状体外释放的影响 黑质网状部和额叶内侧的多巴胺 大脑皮层。据推测，安非他明引起的脑组织改变 后两种结构中的多巴胺释放可能影响纹状体 通过影响神经元的活性间接影响神经化学 皮质纹状体谷氨酸能通路。最后，我们将把 这些发现被纳入了对基础神经化学适应的分析 神经节回路对反复服用苯丙胺的反应。 研究结果将提供有关神经化学的基本信息。 在基底节的相互作用，也将揭示这些 苯丙胺的滥用会改变这种相互作用。这样的理解 肯定会提供对干预的新战略的洞察 药物滥用的药物治疗。

The primary thesis of this research proposal is that the central nervous system alterations that underlie drug taking behaviors involve long-term adaptive phenomena, both within-systems adaptations and between-systems adaptations. Thus, an analysis of drug effects that includes but also extends beyond the primary action of the drug will be fruitful in furthering our understanding of the cellular aspects of drug abuse. Within this framework, we propose a thorough analysis of the effects of amphetamine, a highly abused psychomotor stimulant, upon the neurochemistry of a circuit that includes basal ganglia and associated thalamocortical structures. This circuit potentially is capable of strong influence over psychomotor behaviors. Since the primary action of amphetamine in brain is the release of the neurotransmitter dopamine, the hypothesized within-systems adaptations in this circuit would involve dopamine neurons directly whereas between-systems adaptations would extend to the neurochemical circuits in which dopamine operates. The present experiments make use of the technique of in vivo microdialysis to monitor, in behaving rats, the extracellular concentration of the neurotransmitters dopamine and acetylcholine at several points in this circuit First, we propose to document the impact of amphetamine upon striatal dopamine/acetylcholine dynamics. We will extend our analysis to include the effects of amphetamine on the release of extra-striatal dopamine in substantia nigra pars reticulata and in medial prefrontal cortex. It is hypothesized that amphetamine-induced alterations in dopamine release in these latter structures may influence striatal neurochemistry indirectly by affecting the activity of the corticostriatal glutamatergic pathway. Finally, we will incorporate these findings into an analysis of neurochemical adaptations in basal ganglia circuitry in response to repeated amphetamine administration. The results will provide basic information regarding neurochemical interactions in the basal ganglia and also will reveal how these interactions are altered by amphetamine abuse. Such an understanding surely will provide insight into novel strategies for intervention in the pharmacological treatment of drug abuse.