VTA Glutamate and Orexin Involvement in Cue Reinstatement of Drug Seeking

描述(由申请人提供)：这项建议探索食欲素和谷氨酸传入腹侧被盖区(VTA)在巴甫洛夫线索驱动的恢复可卡因寻找中的作用。在这个药物复发的动物模型中，训练大鼠通过按下杠杆来自我管理可卡因和条件刺激(CS)，然后对这种行为进行熄灭。在稍后的测试日，杠杆压力机会得到与可卡因相关的CS奖励，但没有可卡因。大多数动物强健地恢复已消失的寻药行为，这被认为是恢复暴露于巴甫洛夫药物线索的人类成瘾者的复发模式。VTA多巴胺投射到前脑是药物相关线索促进药物寻找的关键，但控制线索相关VTA放电的输入信息却知之甚少。增食欲素和谷氨酸均促进VTA内的药物寻找和多巴胺细胞放电，内侧前额叶皮质(MPFC)向VTA投射谷氨酸，是CS恢复药物寻找所必需的。此外，增食欲素促进mPFC的谷氨酸输入兴奋VTA多巴胺神经元。在这里，我们建议使用解剖学、免疫组织化学、药理学和行为学技术的组合来检查三个相关的问题。1)可卡因css是否激活mPFC或其他VTA谷氨酸传入Fos，以及这种激活是否与线索触发的可卡因寻求有关？2)VTA中谷氨酸、食欲素或两者的共同激活是触发可卡因相关线索恢复可卡因寻求的必要条件吗？3)同时激活mPFC谷氨酸和VTA的食欲素输入对于CS的恢复是必要的吗？为了解决这些问题，我们使用了Fos和轨迹追踪技术，在VTA内微量注射增食欲素和谷氨酸拮抗剂，并同时灭活mPFC和对侧VTA增食欲素受体的拮抗。许多人想戒毒，但当他们试图戒烟时，又反复复发。一个风险因素是暴露在以前与药物相关的环境线索中，因此了解大脑如何处理这些线索对于开发预防复发的治疗方法至关重要。在这里，我们使用多学科的神经科学技术来研究线索触发的药物寻找恢复的神经电路，进一步加深我们对成瘾的大脑底物的理解。

DESCRIPTION (provided by applicant): This proposal explores the role of orexin and glutamate afferents to the ventral tegmental area (VTA) in Pavlovian cue-driven reinstatement of cocaine seeking. In this animal model of drug relapse, rats are trained to self-administer cocaine plus a conditioned stimulus (CS) by pressing a lever, then are extinguished on this behavior. On later test days, lever presses are rewarded with the cocaine-associated CS, but no cocaine. Most animals robustly reinstate extinguished drug seeking behavior, which is thought to model relapse in recovering human addicts exposed to Pavlovian drug cues. VTA dopamine projections to forebrain are crucial for drug-associated cues to promote drug seeking, yet the inputs controlling cue-related VTA firing are poorly understood. Orexin and glutamate both promote drug seeking and dopamine cell firing in VTA, and medial prefrontal cortex (mPFC) projects glutamatergically to VTA and is necessary for CS reinstatement of drug seeking. Moreover, orexin facilitates excitation of VTA dopamine neurons by glutamate inputs from mPFC. Here, we propose employing a combination of anatomical, immunohistochemical, pharmacological, and behavioral techniques to examine three related questions. 1) Are mPFC or other VTA glutamate afferents Fos activated by cocaine CSs, and is this activation related to cue-triggered cocaine seeking? 2) Are glutamate, orexin, or co-activation of the two in VTA necessary for cocaine-associated cues to trigger reinstatement of cocaine seeking? 3) Is simultaneous activation of mPFC glutamate and orexin inputs to VTA necessary for CS reinstatement? To address these questions, we use Fos and tract tracing techniques, microinjections of orexin and glutamate antagonists in VTA, and simultaneous inactivation of mPFC and contralateral antagonism of VTA orexin receptors. Many people want to quit using drugs, yet repeatedly relapse when they try to quit. One risk factor is exposure to environmental cues previously associated with drugs, so understanding how the brain processes these cues is crucial for development of therapies to prevent relapse. Here we use multidisciplinary neuroscience techniques to examine the neural circuitry of cue-triggered reinstatement of drug seeking, furthering our understanding of the brain substrates of addiction.