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了解和治疗药物滥用障碍的重要贡献者的长期目标。该计划将在肯塔基大学实施，肯塔基大学在跨学科药物滥用方面有着丰富的历史 研究。PI将由Michael Bardo博士指导，并由Greg Gerhardt博士共同指导，这两位博士分别是神经精神药理学和神经化学方面的知名专家。该计划建议使用基于酶的微电极阵列，在临床前大鼠模型中揭示亚秒强直/物理中皮质边缘谷氨酸释放在奖励相关线索的激励显着/价值归因和可卡因强化的个体差异中的作用。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，从而会接近并接触它(手势跟踪器)；另一些动物将刺激用作即将到来的奖励的简单信号，因此会接近将提供奖励的容器(目标跟踪器)。最近的研究表明，手势和目标跟踪上的差异与寻求新鲜感、冲动、对可卡因强化的初始易感性和复发易感性有关。除了皮质边缘多巴胺外，已知刺激奖赏学习和滥用药物还可以改变大脑皮质边缘谷氨酸信号。总体上提出的假设是，激励价值归因的差异是由线索暴露时不同的皮质边缘谷氨酸释放调节的；这种差异释放随后会因反复给药而加剧，导致不同的物质滥用易感性和复发。具体目标1将确定在手势跟踪动物和目标跟踪动物中，每一秒的强效/物理谷氨酸信号是否受到与食物相关的线索的不同影响。具体目标2将确定多巴胺能受体功能在信号/目标跟踪和潜在的紧张性/生理性谷氨酸信号表达中的作用。具体目标3将确定在标记和目标跟踪动物中，每一秒的紧张性和物理性谷氨酸能信号是否与重复给予可卡因自身的不同。然后，专门的目标4将确定多巴胺能受体在可卡因自我给药和手势和目标追踪器中的紧张性/药物性谷氨酸信号中的作用。总而言之，这些结果将深入了解紧张性/生理性谷氨酸信号在刺激奖赏学习、奖赏相关刺激的激励价值归因和可卡因强化中的作用，同时为PI提供这两个领域专家在神经精神药理学和神经化学方面的独特培训。

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.