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: 8457019
• 负责人: Joshua Beckmann
• 金额: $ 13.12万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457019
• 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; Physics; Play; Psychological reinforcement; Rattus; Receptor Inhibition; Recording of previous events; Relapse; Relative (related person); Research; Research Personnel; Resolution; 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; insight; meetings; neurochemistry; novel; pre-clinical; prevent; receptor function; research study; response; skills; substance abuse treatment

DESCRIPTION (provided by applicant): 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/physic 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/physic 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/physic glutamate signaling. Specific Aim 3 will determine if second-by-second tonic and physic 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/physic glutamate signaling in sign- and goal-trackers. Collectively, these results will provide insight into the role of tonic/physic 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.

描述（由申请人提供）：拟议的职业发展计划旨在为PI提供独特的技能和经验，以实现成为一名富有成效，独立的研究人员的短期目标，并成为成为成为重要贡献者的长期目标对药物滥用障碍的理解和治疗。该计划将在肯塔基大学（University of Kentucky 研究。 PI将由Michael Bardo博士进行指导，并由Greg Gerhardt博士（分别是神经心理学和神经化学专家）合作。该计划建议使用基于酶的微电极阵列来揭示在激励性显着性/价值归因的个体差异中，在奖励相关的提示中，在个体差异中释放了下秒的补品/物理中性粘膜谷氨酸的作用，在促预曲率模型中的作用。当刺激可靠地预测奖励时，一些动物将激励价值归因于刺激，从而将其接近并与之接触（签名轨迹）。其他动物将刺激用作即将到来的奖励的简单信号，因此将接近将传递奖励的容器（目标跟踪者）。最近，已经证明，标志和目标跟踪的差异与寻求新颖性，冲动性，对可卡因增强的最初脆弱性和复发脆弱性有关。除了中皮质糖多巴胺外，已知刺激性奖励学习和滥用药物可以改变中皮质糖浆谷氨酸信号传导。总体提出的假设是，激励价值归因的差异是通过提示暴露后的差异中皮质胶质谷氨酸释放介导的。然后，反复的可卡因自我给药会加剧这种差异释放，从而导致差异药物滥用脆弱性和复发。特定的目标1将确定第二次强调/物理谷氨酸信号是否受到签名和目标跟踪动物的食物相关线索的差异影响。具体的目标2将确定多巴胺能受体功能在标志/目标跟踪表达以及潜在的补品/物理谷氨酸信号传导中的作用。特定的目标3将确定在标志和目标跟踪动物中的第二次滋补和物理谷氨酸能信号是否会随重复的可卡因自我给药而差异变化。然后，特定的目标4将确定多巴胺能受体功能在可卡因自我给药以及刺激器和目标跟踪器中的强调/物理谷氨酸信号传导中的作用。总的来说，这些结果将提供有关补品/物理谷氨酸信号传导在刺激奖励学习中的作用，对奖励相关刺激的激励价值归因和可卡因增强的，同时为PI提供了独特的PI培训。 。