Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen

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理解和治疗药物滥用障碍的重要贡献者的长期目标。该计划将在肯塔基州大学进行，该大学在跨学科药物滥用方面有着丰富的历史 research. PI将由Michael Bardo博士和Greg Gerhardt博士共同指导，他们分别是神经精神药理学和神经化学方面的专家。该计划提出使用基于酶的微电极阵列来揭示亚秒强直/中脑皮质边缘谷氨酸释放在临床前大鼠模型中奖励相关线索和可卡因强化的激励显着性/价值归因的个体差异中的作用。当一个刺激可靠地预测奖励时，一些动物将激励价值归因于刺激，因此会接近和接触它（符号追踪者）;其他动物将刺激作为即将到来的奖励的简单信号，因此会接近奖励将被传递的容器（目标追踪者）。最近，它已被证明，在标志和目标跟踪的差异与新奇的寻求，冲动，最初的脆弱性可卡因加固，复发的脆弱性。除了中皮质边缘多巴胺，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。整体提出的假设是，在激励价值归因的差异介导的差异mesocorticolimbic谷氨酸释放线索曝光后，这种差异释放，然后加剧了重复可卡因自我管理，从而引起差异的药物滥用的脆弱性和复发。具体目标1将确定在符号追踪动物与目标追踪动物中，食物相关线索是否对每秒的紧张性/兴奋性谷氨酸信号传导产生不同影响。具体目标2将确定多巴胺能受体功能对信号/目标跟踪表达的作用，以及潜在的紧张性/兴奋性谷氨酸信号传导。具体目标3将确定在信号和目标跟踪动物中的秒接秒的紧张性和神经兴奋性信号传导是否随着重复的可卡因自我给药而发生差异变化。然后，特定目标4将确定多巴胺能受体功能对可卡因自我给药和强直/强直性谷氨酸信号传导在信号和目标跟踪器中的作用。总的来说，这些结果将提供深入了解的作用，强直/谷氨酸信号在刺激奖励学习，奖励相关刺激的激励价值归因，和可卡因的强化，同时提供PI独特的培训，在神经精神药理学和神经化学的专家在这两个领域。

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.