Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen

拟议的职业发展计划旨在为PI提供独特的技能和经验， 满足成为一个生产力，独立的研究人员和成为一个长期目标的短期目标， 为理解和治疗药物滥用障碍做出了重大贡献。该计划将 这项研究是在肯塔基州大学进行的，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， 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紧张性/相性中皮层边缘谷氨酸的作用 奖励相关线索和可卡因的激励显著性/价值归因的个体差异的释放 在临床前大鼠模型中的强化。当刺激可靠地预测奖励时，一些动物会认为 刺激物的刺激值，因此会接近和接触它（标志跟踪器）;其他动物使用 刺激作为即将到来的奖励的简单信号，因此将接近奖励将进入的容器。 “行，行，行。最近，已经证明，在标志和目标跟踪的差异， 与寻求新奇、冲动、对可卡因强化的初始脆弱性和复发脆弱性有关。 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大脑的神经元结构。 中皮质边缘谷氨酸信号传导。总体上提出的假设是，激励价值的差异 归因是由线索暴露时中皮层边缘谷氨酸的差异释放介导的;这 然后通过重复可卡因自身给药加剧差异释放， 药物滥用脆弱性和复发。具体目标1将确定是否每秒强直/相位 谷氨酸信号传导在符号追踪动物和目标追踪动物中受到食物相关线索的不同影响。 特异性目标2将确定多巴胺能受体功能对信号/目标表达的作用。 跟踪和潜在的紧张性/阶段性谷氨酸信号传导。具体目标3将决定是否每秒 紧张性和阶段性信号传导在信号和目标跟踪动物中的变化差异， 反复服用可卡因具体目标4将确定多巴胺能受体的作用， 可卡因自我管理和紧张性/阶段性谷氨酸信号在标志和目标跟踪功能。 总的来说，这些结果将提供深入了解紧张性/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，而 为PI提供神经精神药理学和神经化学方面的独特培训， 领域的

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.