Oxytocin Mediates Phasic and Tonic Dopamine Release

催产素介导阶段性和强直性多巴胺释放

• 批准号: 10575856
• 负责人: Deranda B Lester
• 金额: $ 6.94万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575856
• 关键词: Adult; Affect; Agonist; Anesthesia procedures; Attenuated; Autoreceptors; Brain region; Cell Nucleus; Cells; Clinical; Clinical Trials; Complex; Detection; Diagnosis; Dopamine; Dopamine D2 Receptor; Dopaminergic Cell; Dose; Drug usage; Electrodes; FDA approved; Female; Fire - disasters; Future; Gender; Infusion procedures; Location; Mediating; Mus; Neuropeptides; Nucleus Accumbens; Outcome; Oxytocin; Oxytocin Receptor; Pathway interactions; Patients; Pattern; Periodicity; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Receptor Activation; Recovery; Relapse; Research; Rewards; Scanning; Site; Social Behavior; Socialization; Stimulus; Structure; Substance Use Disorder; System; Techniques; Therapeutic; Therapeutic Effect; Treatment outcome; Ventral Tegmental Area; addiction; behavioral response; biological adaptation to stress; dopaminergic neuron; drug abstinence; drug reward; experience; improved; in vivo; male; meetings; mesolimbic system; neural; neural circuit; neurochemistry; novel; programs; psychostimulant; response; reward processing; sex; social; stimulant use disorder; substance use treatment

Project Summary Substance use disorder (SUD) is prevalent in the US with over 10% of adults fitting the criteria for diagnosis. Unfortunately, SUD treatments are often unsuccessful, with up to 75% of patients experiencing relapse. SUD is associated with problematic reward processing, leading to drug use at the expense of natural rewards and despite negative consequences. Addiction recovery programs often require drug abstinence while reinforcing engagement with natural rewards such as socialization. Research suggests that oxytocin administration could help with this process and improve treatment outcomes for SUD. Although the therapeutic potential of oxytocin is already being investigated in clinical trials with encouraging outcomes, the effects of oxytocin on reward- related neural circuits are not understood. The current proposal will assess the region-specific influence of oxytocin receptor activation on neurochemical release associated with drug and social reward processing. Most studies point to oxytocin decreasing the reinforcing effects of drugs but increasing the salience of social stimuli. The detection of rewarding stimuli is regulated in part by the mesolimbic dopamine system, with dopaminergic cell bodies in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc). Emerging evidence suggests that different circuits facilitate drug versus social reward, with drug reward depending on phasic (fast bursts) dopamine release and social reward on tonic (slow, steady) dopamine release in the NAc. Oxytocin’s therapeutic effects for addiction may be a result of oxytocin shifting dopamine release patterns from phasic to tonic, thus rebalancing the pathways facilitating drug and social reward. The proposed study will be the first to systematically investigate the neural regions in which oxytocin mediates phasic and tonic mesolimbic dopamine release. Using an established electrochemical technique (fast scan cyclic voltammetry), we will assess in vivo phasic and tonic dopamine release following microinfusions of a selective oxytocin receptor agonist into the NAc or VTA. Clarifying the mechanisms by which oxytocin mediates drug and social reward is crucial for harnessing the full therapeutical potential of oxytocin for SUD.

项目摘要 物质使用障碍（SUD）在美国很普遍，超过10%的成年人符合诊断标准。 不幸的是，SUD治疗通常不成功，高达75%的患者会复发。SUD是 与有问题的奖励处理有关，导致以牺牲自然奖励为代价的药物使用， 尽管有负面后果。成瘾恢复计划往往需要戒毒，同时加强 自然奖励，如社会化。研究表明，催产素的管理， 帮助这一过程并改善SUD的治疗结果。尽管催产素的治疗潜力 已经在临床试验中得到了令人鼓舞的结果，催产素对奖励的影响- 相关的神经回路还不清楚。 目前的建议将评估催产素受体激活对神经化学的区域特异性影响， 与药物和社会奖励处理相关的释放。大多数研究指出，催产素降低了 加强药物的效果，但增加社会刺激的显着性。奖励刺激的检测是 部分受中脑边缘多巴胺系统调节，腹侧被盖中有多巴胺能细胞体 区域（VTA）投射到核区（NAc）。新出现的证据表明，不同的电路 促进药物与社会奖励，药物奖励取决于阶段性（快速爆发）多巴胺释放， 社会奖励对NAc中多巴胺的紧张（缓慢，稳定）释放的影响。催产素对成瘾的治疗作用 可能是催产素将多巴胺释放模式从阶段性转变为紧张性的结果，从而重新平衡了 促进药物和社会奖励的途径。 这项拟议中的研究将是第一次系统地调查催产素介导的神经区域 阶段性和紧张性中脑边缘多巴胺释放。使用已建立的电化学技术（快速扫描 循环伏安法），我们将评估在体内阶段性和紧张性多巴胺释放后，微量输注a 选择性催产素受体激动剂进入NAc或VTA。阐明催产素 介导药物和社会奖励对于利用催产素对SUD的全部治疗潜力至关重要。