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: 8214611
• 负责人: Stephen Vincent Mahler
• 金额: $ 2.2万
• 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 2012-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214611
• 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）：本提案探讨了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。在这种药物复发的动物模型中，老鼠被训练通过按下控制杆自我施用可卡因和条件刺激（CS），然后熄灭这种行为。在稍后的测试日，按下杠杆会奖励与可卡因相关的 CS，但不会奖励可卡因。大多数动物都能强有力地恢复已消失的药物寻求行为，这被认为模拟了暴露于巴甫洛夫药物线索的人类成瘾者康复过程中的复发。 VTA 多巴胺对前脑的投射对于促进药物寻求的药物相关线索至关重要，但控制线索相关 VTA 放电的输入却知之甚少。食欲素和谷氨酸都促进 VTA 中的药物寻找和多巴胺细胞放电，内侧前额叶皮层 (mPFC) 向 VTA 投射谷氨酸，对于 CS 恢复药物寻找是必需的。此外，食欲素通过 mPFC 的谷氨酸输入促进 VTA 多巴胺神经元的兴奋。在这里，我们建议结合使用解剖学、免疫组织化学、药理学和行为技术来研究三个相关问题。 1) mPFC 或其他 VTA 谷氨酸传入 Fos 是否被可卡因 CS 激活，这种激活是否与提示触发的可卡因寻找相关？ 2) 谷氨酸、食欲素或两者在 VTA 中的共同激活是否是可卡因相关线索触发可卡因寻求恢复所必需的？ 3) CS 恢复需要同时激活 mPFC 谷氨酸和食欲素输入 VTA 吗？为了解决这些问题，我们使用 Fos 和束追踪技术，在 VTA 中显微注射食欲素和谷氨酸拮抗剂，并同时灭活 mPFC 和对侧 VTA 食欲素受体拮抗剂。 许多人想戒毒，但在尝试戒毒时却屡屡复吸。危险因素之一是接触以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疗法至关重要。在这里，我们使用多学科神经科学技术来检查线索触发的药物寻求恢复的神经回路，进一步加深我们对成瘾的大脑基质的理解。