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

基本信息

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
项目类别：
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

项目摘要

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）：该提案探讨了Orexin和Glutamate传入的作用，以pavlovian提示驱动的可卡因寻求恢复腹腹侧盖区域（VTA）的作用。在这种药物复发的动物模型中，通过按下杠杆来训练大鼠可卡因和条件刺激（CS），然后在这种行为上熄灭。在以后的测试日，杠杆压力机将通过可卡因相关的CS奖励，但没有可卡因。大多数动物坚强地恢复了灭绝的毒品寻求行为，这被认为可以模拟恢复暴露于巴夫洛维亚药物提示的人类成瘾者时的复发。 VTA多巴胺对前脑的预测对于促进药物寻求药物的提示至关重要，但是控制与提示相关的VTA射击的投入知之甚少。在VTA中，Orexin和Glutamate既促进了药物寻求药物和多巴胺细胞的射击，以及内侧前额叶皮层（MPFC）谷氨酸助剂对VTA进行谷氨酸助剂，对于CS恢复药物寻求药物是必不可少的。此外，Orexin促进了MPFC的谷氨酸输入对VTA多巴胺神经元的激发。在这里，我们建议使用解剖学，免疫组织化学，药理和行为技术的组合来检查三个相关问题。 1）MPFC或其他VTA谷氨酸传入FOS是否被可卡因CSS激活，并且这种激活是否与提示触发的可卡因寻求有关？ 2）是否需要可卡因相关的提示引发可卡因寻求可卡因的谷氨酸，甲状腺素，或者两者的VTA中两者的共同激活？ 3）同时激活MPFC谷氨酸和Orexin输入到CS恢复所需的VTA上？为了解决这些问题，我们使用FOS和道追踪技术，VTA中的Orexin和谷氨酸拮抗剂的显微注射，以及MPFC的同时失活以及VTA Orexin受体的对侧拮抗作用。许多人想戒烟，但当他们试图退出时会反复复发。一种危险因素是暴露于先前与药物相关的环境线索，因此了解这些线索如何处理这些提示对于预防疗法的发展至关重要。在这里，我们使用多学科的神经科学技术来检查提示触发药物寻求药物的神经回路，从而进一步了解我们对成瘾的大脑底物的理解。