VTA Glutamate and Orexin Involvement in Cue Reinstatement of Drug Seeking

VTA 谷氨酸和食欲素参与药物寻求提示的恢复

• 批准号: 7805892
• 负责人: Stephen Vincent Mahler
• 金额: $ 4.56万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-25 至 2013-01-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805892
• 关键词: 6-Cyano-7-nitroquinoxaline-2,3-dione; Address; Affect; Amygdaloid structure; Animal Model; Animals; Attenuated; Baclofen; Behavior; Behavioral; Bilateral; Brain; Cells; Cocaine; Conditioned Stimulus; Contralateral; Cues; Dopamine; Drug usage; Excitatory Amino Acid Antagonists; Exposure to; GABA Agonists; Glutamate Receptor; Glutamates; Human; Ipsilateral; Knowledge; Measures; Medial; Mediating; Methods; Microinjections; Modeling; Muscimol; N-Methylaspartate; Neurons; Neurosciences; Pharmaceutical Preparations; Prefrontal Cortex; Procedures; Process; Prosencephalon; Proteins; Randomized; Rattus; Relapse; Rewards; Risk Factors; Role; Self Administration; Self-Administered; Signal Transduction; Source; Staining method; Stains; Stimulus; Structure; System; Techniques; Testing; Time; Tracer; Training; Ventral Tegmental Area; addiction; behavior measurement; behavioral pharmacology; cocaine exposure; dopaminergic neuron; drug relapse; drug seeking behavior; hypocretin; multidisciplinary; neural circuit; prevent; receptor; research study; therapy development

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.

描述（由申请人提供）：本提案探讨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可卡因寻求恢复中的作用。在这个药物复发的动物模型中，老鼠被训练成通过按压杠杆来自我使用可卡因和条件刺激（CS），然后这种行为被消灭。在后来的测试中，按下杠杆的人得到了与可卡因相关的CS，但没有可卡因。大多数动物强烈地恢复了已消失的药物寻求行为，这被认为是人类成瘾者暴露于巴甫洛夫药物线索的复吸过程的模型。前脑的VTA多巴胺投射对药物相关线索促进药物寻找至关重要，但控制线索相关的VTA放电的输入知之甚少。食欲素和谷氨酸均促进VTA的药物寻求和多巴胺细胞放电，内侧前额叶皮层（mPFC）向VTA投射谷氨酸，是CS恢复药物寻求所必需的。此外，食欲素通过来自mPFC的谷氨酸输入促进VTA多巴胺神经元的兴奋。在这里，我们建议采用解剖学、免疫组织化学、药理学和行为学技术的结合来检查三个相关问题。1)可卡因CSs是否激活了mPFC或其他VTA谷氨酸事件，这种激活是否与线索触发的可卡因寻找有关？2)谷氨酸、食欲素或两者在VTA中的共同激活是可卡因相关线索触发可卡因寻求恢复的必要条件吗？3)同时激活mPFC谷氨酸和促食素输入VTA对CS恢复是必要的吗？为了解决这些问题，我们使用Fos和通道追踪技术，在VTA中微量注射食欲素和谷氨酸拮抗剂，同时灭活mPFC和对侧VTA食欲素受体。许多人想要戒掉毒品，然而当他们试图戒掉的时候却反复复发。其中一个风险因素是暴露于先前与药物相关的环境线索，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，我们使用多学科神经科学技术来研究线索触发的药物寻找恢复的神经回路，进一步加深我们对成瘾的大脑基质的理解。