BASAL GANGLIA OUTPUT AND PSYCHOSTIMULANT ABUSE

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于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这些相互作用。暴露于可卡因等精神兴奋剂会导致纹状体神经元基因表达的变化，而纹状体神经元是连接基底神经节和皮质的解剖学回路的一部分。这种分子变化可能会改变这些回路的活动，并似乎在药物诱导的行为变化（如成瘾和依赖）中发挥作用。本研究项目的长期目标是确定纹状体输出神经元中精神兴奋剂诱导的分子变化的功能后果，重点是它们对皮质功能的影响。这项拟议中的研究将通过使用即时早期基因（lEGs）作为功能标记来研究可卡因产生的纹状体输出变化如何影响皮质功能。对于一个，将评估在限定的皮质区域中的IEGs的“基础”表达。此外，感觉运动皮层中的感觉诱发反应（即，由胡须刺激诱发的IEG表达）将作为皮质功能的模型进行检查。拟议的研究将（1）确定并比较急性和重复可卡因治疗对“基础”和感觉诱发的皮质IEG表达的影响。(2)通过纹状体内给予选择性多巴胺受体拮抗剂，评估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。(3)其他研究将调查介导这种基底神经节-皮质调节的解剖学途径。这些研究将进一步加深我们对基底神经节-皮质相互作用机制的理解，并将显示这些相互作用如何被精神兴奋剂可卡因改变。这项工作将有助于建立一个改进的细胞框架，这是理解和成功治疗可卡因成瘾所必需的。

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.