Combined Voltammetry/Electrophysiology in Behaving Rats

行为大鼠的伏安法/电生理学联合分析

• 批准号: 7084605
• 负责人: Regina M Carelli
• 金额: $ 35.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084605
• 关键词: brain electrical activity; brain mapping; brain metabolism; cocaine; computer program /software; craving; dopamine; dopamine antagonists; dopamine receptor; drug addiction; electrochemistry; electrodes; electrophysiology; laboratory rat; neural information processing; neural transmission; neuroanatomy; neuropharmacology; neurotransmitter transport; nucleus accumbens; operant conditionings; personal computers; reinforcer; self medication; substance abuse related behavior

DESCRIPTION (provided by applicant): This is a revised Stage II application written in response to the Program Announcement entitled "Cutting Edge Basic Research Awards" (PA #: PAR-03-017) designed to foster 'high-risk and potentially high-impact' research that will 'advance our understanding of drug abuse and addiction'. The PI has used electrophysiological recording procedures in behaving rats to investigate underlying cellular mechanisms mediating the reinforcing properties of cocaine. One advantage of this approach is that it enables the characterization of nucleus accumbens (Acb) cell firing at crucial times during goal-directed behaviors (see Carelli, 2002; Appendix A). However, one disadvantage of this approach is that the role of dopamine (DA) in reward-related processing can only be indirectly inferred. In contrast, fast scan cyclic voltammetry (FSCV) can be used to directly measure DA in the Acb on a subsecond time scale with micron spatial resolution that provides chemical information temporally analogous to data obtained from unit recording. In this regard, the PI is working in collaboration with Dr. Mark Wightman, an analytical chemist and pioneer in the development and application of FSCV to behaving animals, and has uncovered changes in DA efflux in the Acb during key aspects of drug-taking behavior. Although informative, we cannot make definitive statements about the precise relationship between Acb cell firing and DA since measurements were completed in different animals (and obviously different sites in the Acb). Therefore, our Stage I application was designed to develop the technology to measure changes in Acb cell firing and Acb dopamine from the same electrode in behaving rats. Now complete, four Specific Aims are proposed here to apply this technology. Aim 1 will examine corresponding changes in Acb cell firing and DA during cocaine self-administration in rats. The results of Aim 1 will provide unprecedented information concerning whether subsecond changes in DA correlate with Acb activity that encode cocaine-seeking behaviors. Aim 2 will use the combined technique to determine the contribution of phasic DA to the associative properties of Acb cell firing documented by the PI. This study will provide the first direct evidence that phasic DA may play a role in activating Acb neurons that process information about cocaine-associated stimuli. Aim 3 will expand information gained in Aims 1 & 2 and examine Acb cell firing and subsecond changes in DA during goal-directed behaviors for 'natural' (water) reinforcement. Finally, Aim 4 will expand information gained above by iontophoretic (local) application of drug in conjunction with the combined technique during self-administration. This study will provide evidence that changes in Acb firing patterns are the result of phasic DA and determine the involvement of specific DA receptors in this process.

描述（由申请人提供）：这是一项经过修订的II期申请，以响应题为“尖端基础研究奖”的计划公告（PA＃：PAR-03-017），旨在促进“高风险和潜在的高影响力”研究，以“提高我们对药物滥用和成瘾的理解”。 PI在行为大鼠中使用了电生理记录程序来研究介导可卡因增强特性的潜在细胞机制。这种方法的一个优点是，它可以在目标定向行为的关键时期在关键时期的伏隔核（ACB）细胞发射（参见Carelli，2002;附录A）。但是，这种方法的一个缺点是，只能间接推断出多巴胺（DA）在与奖励相关的处理中的作用。相比之下，快速扫描循环伏安法（FSCV）可用于以微分空间分辨率在次级时间尺度上直接测量ACB中的DA，从而提供了与从单位记录获得的数据相似的化学信息。在这方面，PI正在与Mark Wightman博士合作，Mark Wightman博士是FSCV开发和应用在行为动物中的先驱，并且在吸毒行为的关键方面发现了ACB中DA外排的变化。尽管内容丰富，但我们不能对ACB细胞发射和DA之间的确切关系做出确切的陈述，因为在不同的动物（ACB中显然不同的地点）完成了测量。因此，我们的阶段I应用旨在开发该技术，以测量行为大鼠中同一电极的ACB细胞发射和ACB多巴胺的变化。现在完成，这里提出了四个具体目标来应用这项技术。 AIM 1将检查大鼠可卡因自我给药期间ACB细胞发射和DA的相应变化。 AIM 1的结果将提供有关DA中的子秒变化是否与编码可卡因寻求可卡因行为的ACB活动相关的前所未有的信息。 AIM 2将使用合并的技术来确定阶段DA对PI记录的ACB细胞发射的关联特性的贡献。这项研究将提供第一个直接证据，表明阶段DA可能在激活ACB神经元中发挥作用，以处理有关可卡因相关刺激的信息。 AIM 3将扩大在目标1和2中获得的信息，并检查目标指导行为的“自然”（水）增强行为期间DA的ACB细胞射击和次要变化。最后，AIM 4将通过在自我管理过程中与联合技术结合使用药物（局部）药物应用来扩展信息。这项研究将提供证据表明ACB发射模式的变化是阶段DA的结果，并确定特定DA受体参与此过程。