Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen

激励显着性和可卡因强化剂中的补品和阶段性谷氨酸释放

• 批准号: 9131675
• 负责人: Joshua Beckmann
• 金额: $ 24.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131675
• 关键词: Abstinence; Addictive Behavior; Affect; Animals; Behavior; Cell Nucleus; Chronic; Cocaine; Control Animal; Cues; Development; Development Plans; Disease; Dopamine; Dopamine Antagonists; Dopamine Receptor; Enzymes; Exhibits; Food; Glutamates; Goals; Impulsivity; Incentives; Individual; Individual Differences; Institution; Kentucky; Learning; Maintenance; Mediating; Mentors; Microdialysis; Microelectrodes; Modeling; Neurons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Psychological reinforcement; Rattus; Receptor Inhibition; Recording of previous events; Relapse; Research; Research Personnel; Rewards; Role; Schedule; Self Administration; Self-Administered; Signal Transduction; Stimulus; Substance Use Disorder; Substance abuse problem; Technology; Time; Training; Universities; awake; base; career development; classical conditioning; cocaine exposure; design; drug of abuse; experience; glutamatergic signaling; incentive salience; insight; meetings; neurochemistry; neuropsychopharmacology; novel; pre-clinical; prevent; receptor function; research study; response; skills; substance abuse treatment; temporal measurement

The proposed career development plan is designed to provide the PI with a unique skill set and experience to meet the short-term goal of becoming a productive, independent researcher and long-term goal of becoming a significant contributor to the understanding and treatment of substance abuse disorders. The plan will be carried out at the University of Kentucky, an institution with a rich history of interdisciplinary substance abuse research. The PI will be mentored by Dr.Michael Bardo and co-mentored by Dr. Greg Gerhardt, established experts in neuropsychopharmacology and neurochemistry, respectively. The plan proposes to use enzyme- based microelectrode arrays to uncover the role of sub-second tonic/phasic mesocorticolimbic glutamate release in individual differences in incentive salience/value attribution to reward-related cues and cocaine reinforcement in a preclinical rat model. When a stimulus reliably predicts reward, some animals attribute incentive value to the stimulus, and thus will approach and contact it (sign-trackers); other animals use the stimulus as a simple signal of forthcoming reward, and thus will approach the receptacle into which reward will be delivered (goal-trackers). Recently, it has been demonstrated that differences in sign and goal tracking are related to novelty seeking, impulsivity, initial vulnerability to cocaine reinforcement, and relapse vulnerability. In addition to mesocorticolimbic dopamine, stimulus-reward learning and drugs of abuse are known to alter mesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive value attribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; this differential release is then exacerbated by repeated cocaine self-administration, giving rise to differential substance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/phasic glutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals. Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal- tracking, and underlying tonic/phasic glutamate signaling. Specific Aim 3 will determine if second-by-second tonic and phasic glutamatergic signaling in sign- and goal-tracking animals changes differentially with repeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptor function on cocaine self-administration and tonic/phasic glutamate signaling in sign- and goal-trackers. Collectively, these results will provide insight into the role of tonic/phasic glutamate signaling in stimulus- reward learning, incentive value attribution to reward-associated stimuli, and cocaine reinforcement, while providing the PI with unique training in neuropsychopharmacology and neurochemistry by experts in both fields.

拟议的职业发展计划旨在为 PI 提供独特的技能和经验 满足成为一名富有成效的独立研究人员的短期目标和成为一名 对理解和治疗药物滥用障碍做出了重大贡献。该计划将是 肯塔基大学是一所拥有丰富的跨学科药物滥用历史的机构 研究。 PI 将由 Michael Bardo 博士指导，并由 Greg Gerhardt 博士共同指导，成立 分别是神经精神药理学和神经化学专家。该计划建议使用酶- 基于微电极阵列揭示亚秒强直/阶段性中皮质边缘谷氨酸的作用 释放奖励相关线索和可卡因的激励显着性/价值归因的个体差异 临床前大鼠模型中的强化。当刺激可靠地预测奖励时，一些动物会归因 对刺激的激励价值，因此会接近并接触它（信号跟踪器）；其他动物使用 刺激作为即将到来的奖励的简单信号，因此会接近奖励将进入的容器 交付（目标跟踪器）。最近，已经证明标志和目标跟踪的差异 与寻求新奇、冲动、最初对可卡因强化的脆弱性和复发脆弱性有关。 除了中皮质边缘多巴胺外，已知刺激奖励学习和滥用药物也会改变 中皮质边缘谷氨酸信号传导。总体提出的假设是激励价值的差异 归因是由线索暴露时中皮质边缘谷氨酸释放的差异介导的；这 然后，重复的可卡因自我给药加剧了差异释放，从而产生了差异释放 药物滥用的脆弱性和复发。具体目标 1 将确定是否逐秒进行强直/阶段 在信号追踪动物和目标追踪动物中，谷氨酸信号传导受到食物相关线索的不同影响。 具体目标 2 将确定多巴胺能受体功能对符号/目标表达的作用 跟踪和潜在的强直/阶段性谷氨酸信号传导。具体目标 3 将确定是否逐秒 信号跟踪和目标跟踪动物的强直和阶段性谷氨酸信号变化随 反复自我注射可卡因。具体目标 4 将确定多巴胺能受体的作用 对可卡因自我给药以及信号和目标跟踪器中的强直/阶段性谷氨酸信号传导的作用。 总的来说，这些结果将深入了解强直/阶段性谷氨酸信号在刺激中的作用。 奖励学习、奖励相关刺激的激励价值归因和可卡因强化，同时 由神经精神药理学和神经化学领域的专家为 PI 提供独特的培训 字段。