Oxytocin projections mediate social and drug reward

催产素预测介导社会和药物奖励

• 批准号: 10654438
• 负责人: Deranda B Lester
• 金额: $ 36.27万
• 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: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654438
• 关键词: Adult; Affect; Area; Attenuated; Autoreceptors; Brain region; CRISPR/Cas technology; Cells; Clinical Trials; Cocaine; Code; Complex; Detection; Diagnosis; Dopamine; Dopamine D2 Receptor; Dopaminergic Cell; Down-Regulation; Drug usage; Equilibrium; FDA approved; Female; Genetic; Injections; Measurement; Mediating; Mentors; Mus; Neural Pathways; Neurons; Neuropeptides; Neurosciences; Nucleus Accumbens; Outcome; Oxytocin; Oxytocin Receptor; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Receptor Activation; Recovery; Relapse; Research; Rewards; Role; Sensory Receptors; Site; Social Conditions; Socialization; Stimulus; Structure; Substance Use Disorder; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Treatment outcome; Ventral Tegmental Area; addiction; career; conditioned place preference; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drug abstinence; drug reward; experience; improved; in vivo; insight; male; mesolimbic system; neural circuit; neuromechanism; novel; paraventricular nucleus; preference; programs; promoter; psychostimulant; response; reward processing; sex; skills; social; stimulant use disorder; substance use treatment; therapeutically effective; undergraduate student

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. 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 current proposal will assess the role of oxytocin projections and oxytocin receptors located in reward-related brain regions on preference for drug vs social reward and phasic vs tonic dopamine release. The proposed study will be the first to systematically investigate the neural pathways and receptor sites utilized by oxytocin to mediate reward processing. The proposed study incorporates contemporary techniques for manipulating neural circuits (DREADD and CRISPR/Cas9 technologies) and inventive twists on conditioned place preference testing and in vivo dopamine quantification. 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治疗往往不成功，高达75%的患者复发。苏德是 与有问题的奖赏处理有关，导致以牺牲自然奖赏和 尽管有负面后果。成瘾康复计划通常需要戒毒，同时加强 参与自然的回报，如社交。研究表明，服用催产素可能会 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 已经在临床试验中进行了研究，结果令人鼓舞，催产素对奖赏的影响- 相关的神经回路尚不清楚。 大多数研究指出，催产素降低了药物的增强作用，但增加了社会关注 刺激物。奖赏刺激的检测部分受中脑边缘多巴胺系统的调节， 腹侧被盖区(VTA)的多巴胺能胞体投射到伏核(NAC)。 新出现的证据表明，不同的回路促进了药物与社会奖励之间的关系，其中包括药物奖励 取决于时相(快速爆发)多巴胺的释放和对强效(缓慢、稳定)多巴胺的社会奖励 在南汽释放。催产素对成瘾的治疗作用可能是催产素改变多巴胺的结果 从阶段到主位释放模式，从而重新平衡促进药物和社会奖励的途径。这个 目前的提案将评估位于奖赏相关区域的催产素投射和催产素受体的作用 大脑中偏爱药物和社会奖励的区域，以及时相和紧张性多巴胺释放的区域。 这项拟议的研究将是第一次系统地研究神经通路和利用的受体位置。 通过催产素来调节奖赏的处理。这项拟议的研究结合了现代技术 操纵神经电路(DREADD和CRISPR/CAS9技术)和对条件反射的创造性扭曲 位置偏爱测试和体内多巴胺定量。阐明催产素的作用机制 中介药物和社会奖励对于充分利用催产素对SUD的治疗潜力至关重要。