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: 8309441
• 负责人: Regina M Carelli
• 金额: $ 31.75万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309441
• 关键词: Abstinence; Address; Animals; Aversive Stimulus; Award; Basic Science; Behavior; Brain; Cells; Chemicals; Cocaine; Cocaine Abuse; Cocaine Dependence; Collaborations; Cues; Data; Development; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Electrochemistry; Electrodes; Electrophysiology (science); Event; Exhibits; Food; Funding; Goals; Grant; Health; Human; Infusion procedures; Interruption; Iontophoresis; Learning; Link; Location; Measurement; Measures; Mediating; Methodology; Methods; Neuronal Plasticity; Neurons; Nucleus Accumbens; Oral; Pattern; Pharmaceutical Preparations; Procedures; Process; Progress Reports; Quinine; Rattus; Relative (related person); Reporting; Research; Resolution; Rewards; Role; Scanning; Schedule; Self Administration; Self Stimulation; Signal Transduction; Site; Structure; Sucrose; Techniques; Technology; Testing; Time; United States; Water; Work; brain cell; design; drug abstinence; experience; improved; information processing; insight; neuroadaptation; neurobiological mechanism; reinforcer; relating to nervous system

DESCRIPTION (provided by applicant): Numerous studies implicate a critical role of the nucleus accumbens (NAc) and its dopaminergic input in goal-directed behavior for cocaine and 'natural' (e.g., food/water) rewards. The PI has used electrophysiological recording procedures in behaving rats to investigate underlying cellular mechanisms mediating reward-seeking behavior. To examine the role of dopamine (DA) in this process, fast scan cyclic voltammetry (FSCV) was used, a technique that allows direct measurement of DA in the NAc on a subsecond time scale with micron spatial resolution. Thus, FSCV provides chemical information temporally analogous to data obtained from electrophysiology. Working with R. Mark Wightman, changes in DA efflux were uncovered in the NAc during key aspects of reward-seeking involving natural rewards (e.g., sucrose), intracranial self-stimulation (ICSS) and cocaine self-administration. In order to make definitive statements about the relationship between specific types of cellular discharges and DA, this grant was originally submitted as a "Cutting Edge Basic Research Award" to develop and apply the technology to measure changes in NAc cell firing and NAc DA from the same electrode in behaving rats. This combined approach enabled the first unique view of real-time, spatially resolved concentration fluctuations of DA in conjunction with changes in cell firing during behavior. In the last funding period key factors were determined that control rapid DA signaling (using FSCV alone) and its relationship to NAc cell firing during behavior (using the combined technique). Here, 4 specific aims are proposed to build upon that work. Aim1 will use FSCV alone to determine if rapid DA release is altered during a cocaine/sucrose multiple schedule when animals switch from responding for one versus the other reward. Thus, we will determine if DA release within specific locations occurs uniformly during operant responding for both rewards, or if distinct subregions exist in the NAc at which DA release selectively occurs depending upon reinforcer type. Aim 2 will build upon prior work by the PI and determine the effects of interruption of drug access (cocaine abstinence) on rapid DA signaling in the NAc. Our prior electrophysiology studies revealed a heightened activation of NAc cell firing following 1-month cocaine abstinence. Here, we will incorporate drug abstinence and reinstatement procedures to determine if interruption of cocaine self-administration enhances rapid DA release during subsequent cocaine-seeking behavior. Although the NAc is clearly linked with reward, less is known about its role in aversion. Aim 3 will use the combined voltammetry/electrophysiology technique to determine the precise relationship between rapid DA signaling and NAc cell firing during intra-oral infusions of a rewarding (sucrose) vs. aversive (quinine) tastant. Aim 4 will expand that study and apply our improved iontophoresis method in conjunction with the combined voltammetry/electrophysiology technology to determine potential causal links between rapid DA signaling and NAc cell firing during rewarding and aversive situations. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a serious problem in the United States, yet strategies to treat cocaine abuse are limited. The significance of this research is that it will provide unprecedented information regarding the actions of rewarding (e.g., cocaine) and aversive substances on dopamine release and the activity of brain cells in the nucleus accumbens (NAc), a brain structure known to be crucially involved in mediating the reinforcing actions of abused substances. The information obtained from the present application will provide insight into the neurobiological mechanisms mediating cocaine addiction and thereby aid in the development of pharmacological agents to treat human drug addiction.

描述（由申请人提供）：大量研究暗示了伏隔核（NAC）及其多巴胺能输入可卡因和“自然”（例如食品/水）奖励中的多巴胺能输入。 PI在行为大鼠中使用电生理记录程序来研究介导寻求奖励行为的基本细胞机制。为了检查多巴胺（DA）在此过程中的作用，使用了快速扫描循环伏安法（FSCV），该技术允许在Micron空间分辨率下在NAC中直接测量NAC中的DA。因此，FSCV提供了与从电生理学获得的数据相似的化学信息。在与R. Mark Wightman合作的情况下，在涉及自然奖励（例如蔗糖），颅内自我刺激（ICS）和可卡因自我管理的主要方面，在NAC中发现了DA外排的变化。为了对特定类型的细胞放电与DA之间的关系作出确定的陈述，该赠款最初是作为“尖端基础研究奖”提交的，以开发和应用该技术来衡量行为大鼠中同一电极的NAC细胞发射和NAC DA的变化。这种合并的方法使DA的实时，空间分辨浓度波动的第一个独特视图与行为过程中细胞发射的变化结合使用。在最后的资金期间，关键因素是确定控制快速DA信号（仅使用FSCV）及其在行为过程中与NAC细胞发射的关系（使用组合技术）。在这里，提出了4个具体目标来基于这项工作。 AIM1将仅使用FSCV来确定当动物从响应一个而不是另一个奖励的情况下，在可卡因/蔗糖的多个时间表中，在可卡因/蔗糖多重时间表中是否会改变快速DA的释放。因此，我们将确定在对两个奖励的操作响应期间，在特定位置内释放是否均匀地发生，还是在NAC中存在不同的子区域，在该NAC中，DA释放选择性地释放取决于增强器类型。 AIM 2将基于PI先前的工作，并确定药物获取中断（可卡因禁欲）对NAC快速DA信号的影响。我们先前的电生理研究表明，1个月可卡因戒酒后，NAC细胞发射的激活增加。在这里，我们将结合药物的戒毒和恢复程序，以确定可卡因自我给药的中断是否会在随后的可卡因寻求可卡因行为期间增强了快速DA的释放。尽管NAC显然与奖励有关，但对其在厌恶中的作用知之甚少。 AIM 3将使用合并的伏安/电生理技术来确定在奖励（蔗糖）与厌恶（quinine）味道的口腔内输注期间快速DA信号传导与NAC细胞发射之间的精确关系。 AIM 4将扩展该研究，并将我们改进的离子噬菌学方法与伏安级/电生理技术结合使用，以确定在奖励和厌恶情况下快速DA信号传导与NAC细胞发射之间的潜在因果关系。公共卫生相关性：可卡因成瘾在美国是一个严重的问题，但是治疗可卡因滥用的策略有限。这项研究的意义在于，它将提供有关奖励（例如可卡因）和厌恶性物质对多巴胺释放的作用的前所未有的信息，以及伏隔核（NAC）中脑细胞的活性，这是一种已知的大脑结构，这是一种至关重要的，与介导被滥用物质的增强作用有关。从本应用中获得的信息将提供有关介导可卡因成瘾的神经生物学机制，从而有助于开发药理学剂以治疗人类药物成瘾。