BASAL GANGLIA OUTPUT AND PSYCHOSTIMULANT ABUSE

基底神经节输出和精神兴奋剂滥用

• 批准号: 7013168
• 负责人: Heinz Steiner
• 金额: $ 25.97万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013168
• 关键词: autoradiography; basal ganglia; behavior test; central nervous system stimulants; cerebral cortex; cocaine; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse; drug addiction; evoked potentials; gene expression; genetic regulation; in situ hybridization; laboratory rat; neurons; neuropsychology; occipital lobe /cortex; psychological reinforcement; regulatory gene; sensory mechanism; substance P

DESCRIPTION (provided by applicant): Interactions between the basal ganglia and the cerebral cortex are critical for the organization of motivated behavior and are implicated in psychostimulant addiction. Dopamine in the striatum regulates these interactions. Exposure to psychostimulants such as cocaine produces changes in gene expression in striatal neurons that are part of the anatomical circuits that interconnect the basal ganglia and the cortex. Such molecular changes likely alter activity in these circuits and seem to play a role in drug-induced behavioral changes such as addiction and dependence. The long-term objective of this research project is to determine functional consequences of psychostimulant-induced molecular changes in striatal output neurons, with focus on their effects on cortical function. The proposed research will investigate how changes in striatal output produced by cocaine affect cortical function, by using immediate-early genes (lEGs) as functional markers. For one, "basal" expression of lEGs in defined cortical regions will be assessed. In addition, sensory-evoked responses in the sensorimotor cortex (i.e., lEG expression evoked by whisker stimulation) will be examined as a model of cortical function. The proposed studies will (1) determine and compare the effects of acute and repeated cocaine treatment on "basal" and sensory-evoked cortical lEG expression. (2) The relative contributions of D1- and D2 dopamine receptor-regulated striatal outputs to these cortical effects will be assessed by intrastriatal administration of selective dopamine receptor antagonists. (3) Other studies will investigate the anatomical pathways that mediate this basal ganglia-cortical regulation. These studies will further our understanding of the mechanisms that govern basal ganglia-cortical interactions and will show how these interactions are changed by the psychostimulant cocaine. This work will help establish an improved cellular framework necessary to understand and successfully treat cocaine addiction.

描述（由申请人提供）：基底神经节和大脑皮层之间的相互作用对动机行为的组织至关重要，并与精神兴奋剂成瘾有关。纹状体中的多巴胺调节着这些相互作用。暴露于像可卡因这样的精神兴奋剂中，纹状体神经元的基因表达会发生变化，纹状体神经元是连接基底神经节和皮层的解剖回路的一部分。这种分子变化可能会改变这些神经回路的活动，并似乎在药物引起的行为改变（如成瘾和依赖）中发挥作用。本研究项目的长期目标是确定精神兴奋剂诱导纹状体输出神经元分子变化的功能后果，重点是它们对皮质功能的影响。拟议的研究将通过使用即时早期基因（腿部）作为功能标记来研究可卡因产生的纹状体输出的变化如何影响皮质功能。首先，将评估确定的皮质区域中lEGs的“基础”表达。此外，感觉运动皮层的感觉诱发反应（即由须刺激引起的lEG表达）将作为皮质功能的模型进行检查。拟议的研究将(1)确定和比较急性和反复可卡因治疗对“基础”和感觉诱发的皮质lEG表达的影响。(2) D1和D2多巴胺受体调节的纹状体输出对这些皮质效应的相对贡献将通过在纹状体内施用选择性多巴胺受体拮抗剂来评估。(3)其他研究将探讨基底神经节-皮质调节的解剖学途径。这些研究将进一步加深我们对控制基底神经节-皮层相互作用机制的理解，并将显示这些相互作用是如何被精神兴奋剂可卡因改变的。这项工作将有助于建立一个更好的细胞框架，这是理解和成功治疗可卡因成瘾所必需的。