NEUROCHEMICAL PLASTICITY AND DRUG RESPONSES--AMPHETAMINE

这项研究的主要论点是，中枢神经系统 作为药物服用行为基础的系统改变涉及长期的 适应现象，包括系统内适应和系统间适应 适应 因此，药物作用的分析，包括但也 超越药物的主要作用将是富有成效的， 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，我们提出了一个彻底的分析的影响， 安非他明，一种高度滥用的精神兴奋剂， 包括基底神经节和相关的回路的神经化学 丘脑皮质结构 该电路可能能够 对心理行为的强烈影响。 由于主要行动的 安非他明在大脑中是神经递质多巴胺的释放， 假设在这个回路中的系统内适应将涉及 多巴胺神经元直接，而系统间适应将 延伸到多巴胺运作的神经化学回路。 的 本实验利用体内微透析技术， 监测，在行为大鼠，细胞外浓度的 神经递质多巴胺和乙酰胆碱在这几个点， 首先，我们建议记录安非他明对 纹状体多巴胺/乙酰胆碱动力学。 我们将分析扩展到 包括安非他明对纹状体外 黑质网状部和内侧前额叶多巴胺 皮层 据推测，安非他明诱导的改变， 这些结构中的多巴胺释放可能会影响纹状体 神经化学间接影响的活动， 皮质纹状体多巴胺能通路 最后，我们将 将这些发现用于分析基底神经细胞的神经化学适应， 神经节回路对反复服用安非他明的反应。 结果将提供有关神经化学的基本信息 在基底神经节的相互作用，也将揭示如何这些 安非他明滥用改变了相互作用。 这样的理解 肯定会提供深入了解新的战略干预， 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.