Ventral Periaqueductal Gray Dopamine Control of Sleep and Arousal

腹侧导水管周围灰色多巴胺控制睡眠和觉醒

• 批准号: 9902961
• 负责人: Chicora F Oliver
• 金额: $ 7.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-31 至 2020-02-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902961
• 关键词: AMD3100; Abstinence; Address; Amphetamines; Animals; Arousal; Attenuated; Award; Bathing; Behavior; Brain; CXCL12 gene; CXCR4 gene; Cell Culture Techniques; Cells; Cocaine; Cocaine Users; Collaborations; Computer Assisted; Data; Dendrites; Development; Discipline; Dopamine; Electrophysiology (science); Ethics; FDA approved; Foundations; Funding; Genes; Glutamates; Goals; Golgi Apparatus; Grant; Human; Immunohistochemistry; Inflammatory; Institution; Knowledge; Learning; Ligands; Link; Measures; Mediating; Mentors; Messenger RNA; Methamphetamine; Morphology; Neuronal Plasticity; Neurons; Neurosciences; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological; Plasma; Postdoctoral Fellow; Pre-Clinical Model; Preparation; Property; Proteins; Psychostimulant dependence; Public Health; Publishing; Recording of previous events; Relapse; Research; Research Personnel; Research Project Grants; Rewards; Rodent; Rodent Model; Self Administration; Sodium Chloride; Stains; Structure; Substance abuse problem; System; Techniques; Time; Training; Ultrasonics; Ventral Tegmental Area; Western Blotting; Work; Writing; addiction; base; brain behavior; career; career development; chemokine; chemokine receptor; electrical property; field study; innovation; midbrain central gray substance; neuroinflammation; novel; patch clamp; preference; psychostimulant; receptor; reconstruction; research study; sleep regulation; stimulant abuse; student mentoring; symposium; therapeutic target; vocalization

PROJECT ABSTRACT Psychostimulant abuse is a major public health concern, yet no FDA-approved therapies exist. 3,4-methylenedioxypyrovalerone (MDPV) is a type of `bath salt' that is ten times stronger, but mechanistically similar, to cocaine. This psychostimulant has powerful reinforcing effects that manifest as escalating self-administration and relapse following abstinence. Chemokines, chemotactic inflammatory proteins, are dysregulated in cocaine users. The chemokine receptor- ligand pair CXCR4-CXCL12 in particular has been linked to psychostimulant use. Human cocaine users and rodent models have heightened plasma CXCL12 levels, and CXCL12 potentiates the dopaminergic and hyperlocomotive effects of cocaine. Through mastery of rodent self-administration, I have expanded my technical repertoire and revealed that AMD3100, a CXCR4 antagonist, decreases cocaine and MDPV-induced hyperlocomotion, self- administration, and conditioned place preference, reflecting a reduction in the reinforcing effects of MDPV. Moreover, repeated MDPV increases CXCL12 and CXCR4 mRNA in the ventral tegmental area and decreases dendrite morphometrics in the nucleus accumbens (NAC) core. These findings strongly implicate that CXCR4 modulation alters the reinforcing and neuroplastic effects of MDPV. F99 phase research studies will extend these findings by measuring dendrite morphology and neuroelectrical properties of the NAC core following AMD3100 treatment and MDPV self-administration sessions. Structural plasticity will be examined using a Golgi-Cox stain followed by computer-assisted neuron reconstruction. Whole cell patch clamp will be mastered to examine NAC core electrical property dynamics and glutamatergic drive. Learning these electrophysiological techniques will expanding my technical repertoire, elucidate the effects of MDPV self-administration on structural neuroelectrical plasticity in the NAC core, and promote my ultimate career goal of becoming an independent neuroscience researcher. The results of these studies may reveal modulation of the receptor-ligand CXCR4-CXCL12 system as a therapeutic target for treatment of psychostimulant addiction. Finally, the proposed project will provide a foundation upon which a postdoctoral research focus on substance abuse can be built, in preparation for a career as an independent neuroscience researcher.

项目摘要 精神兴奋剂滥用是一个主要的公共卫生问题，但尚无 FDA 批准的治疗方法 存在。 3,4-亚甲基二氧基吡咯戊酮 (MDPV) 是一种“浴盐”，其强度是其十倍， 但在机制上与可卡因相似。这种精神兴奋剂具有强大的强化作用 表现为自我管理升级和戒断后复发。趋化因子， 趋化性炎症蛋白在可卡因使用者中失调。趋化因子受体—— 配体对 CXCR4-CXCL12 特别与精神兴奋剂的使用有关。人类 可卡因使用者和啮齿动物模型的血浆 CXCL12 水平升高，并且 CXCL12 增强可卡因的多巴胺能和过度运动作用。通过掌握 啮齿类动物的自我管理，我扩展了我的技术储备并揭示了 AMD3100 是一种 CXCR4 拮抗剂，可减少可卡因和 MDPV 诱导的过度运动、自我 行政管理和条件性地点偏好，反映了强化效应的减少 的MDPV。此外，重复 MDPV 会增加腹侧 CXCL12 和 CXCR4 mRNA 被盖区并减少伏隔核（NAC）核心的树突形态。 这些发现强烈暗示 CXCR4 调节改变了强化和神经可塑性 MDPV 的影响。 F99 阶段研究将通过测量枝晶来扩展这些发现 AMD3100 处理后 NAC 核心的形态和神经电特性 MDPV 自我管理课程。将使用高尔基-考克斯 (Golgi-Cox) 检查结构可塑性 染色后进行计算机辅助神经元重建。全细胞膜片钳将 掌握了检查 NAC 核心电特性动力学和谷氨酸驱动。学习 这些电生理学技术将扩展我的技术能力，阐明 MDPV 自我给药对 NAC 核心结构神经电可塑性的影响，以及 促进我成为一名独立神经科学研究人员的最终职业目标。这 这些研究的结果可能揭示受体-配体 CXCR4-CXCL12 系统的调节 作为治疗精神兴奋剂成瘾的治疗靶点。最后，建议的项目 将为专注于药物滥用的博士后研究奠定基础 建造，为独立神经科学研究人员的职业生涯做准备。