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Dysregulation of midbrain GABAergic circuitry contributes to the motivational properties of cocaine

中脑 GABA 能回路的失调导致可卡因的动机特性

基本信息

批准号：
10611966
负责人：
Alexey Ostroumov
金额：
$ 15.93万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10611966
关键词：
Acute Addictive Behavior American Animal Model Animals Anions Area Attenuated Behavior Brain Brain region Cessation of life Characteristics Chlorides Cocaine Cocaine Abuse Cocaine Dependence Cocaine use disorder Data Development Down-Regulation Drug Targeting Drug Use Disorder Functional disorder Future Goals Health Human Impairment In Vitro Intake Label Lateral Learning Measures Medial Mediating Mentorship Methods Midbrain structure Modeling Molecular Motivation Neurons Nucleus Accumbens Pathologic Pathway interactions Pharmaceutical Preparations Pharmacotherapy Physiology Play Population Property Public Health Publishing Rat Transgene Rattus Receptor Activation Reporting Research Rewards Rodent Role Self Administration Signal Transduction Slice Substance Use Disorder Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Therapeutic Training Ventral Tegmental Area Viral Work addiction cell type cellular targeting cocaine exposure cocaine overdose cocaine related behaviors cocaine self-administration cocaine use cost designer receptors exclusively activated by designer drugs dopaminergic neuron effective therapy experimental study gamma-Aminobutyric Acid genetic approach mesolimbic system neural circuit neural repair neuroadaptation neuropsychiatric disorder novel overdose death pharmacologic receptor reward circuitry synaptic inhibition therapeutic target tool translational model

项目摘要

Cocaine addiction remains a major public health problem in the US, but effective treatments are still lacking. Cocaine use disorder is characterized by the development of pathological motivation for cocaine, characterized by intake in the face of rising costs and harmful consequences. Decreasing excessive motivational importance of drug taking without altering motivation for natural rewards is among the major goals of treating cocaine addiction. However, development of new pharmacotherapies requires understanding the basic brain mechanisms underlying cocaine addiction. Identifying these mechanisms is timely because cocaine use and overdoses have been increasing over the last several years. A growing body of evidence indicates that midbrain circuits play a critical role in cocaine-related behaviors. My preliminary data in rodents indicate that cocaine, but not sucrose, dysregulates midbrain inhibitory circuitry via decreased function of anion transporter, KCC2, located in VTA GABA neurons. This form of cocaine-induced neuroadaptation in GABAergic signaling has not been described previously, and I plan to investigate its impact on cocaine self-administration in rats. Given my preliminary findings suggesting that KCC2 dysfunction contributes to motivational properties of cocaine, I will measure motivation for cocaine self- administration while manipulating KCC2 activity in the VTA. At the cellular level, KCC2 dysfunction attenuates GABAA receptor-mediated inhibition leading to hyperexcitability of VTA GABA neurons. To assess the role of VTA GABA neurons in cocaine motivation, I will use chemogenetic approach in transgenic rat model to directly manipulate neuronal activity during cocaine self-administration. Ultimately, I will test if cocaine dysregulates GABAergic signaling in a circuit-specific manner. Accumulated evidence indicates that VTA GABA neurons project to multiple brain areas and I will focus on GABAergic projection to the nucleus accumbens, a brain region critically involved in motivational properties of addictive drugs. I will label specific VTA GABA projections to the medial and lateral shell of the nucleus accumbens and test the effect of cocaine on GABAergic signaling in these projections. Taken together, the research will illuminate the role of midbrain GABAergic circuitry in the pathological motivation for cocaine.

可卡因成瘾仍然是美国的一个主要公共卫生问题，但有效的治疗方法仍然存在。缺乏可卡因使用障碍的特征是可卡因的病理性动机的发展，其特点是在面临成本上升和有害后果的情况下摄入。减少过度在不改变自然奖励动机的情况下，吸毒的动机重要性是主要目标之一治疗可卡因成瘾然而，开发新的药物疗法需要了解可卡因成瘾的基本大脑机制确定这些机制是及时的，因为可卡因在过去几年中，吸毒和过量的情况一直在增加。越来越多的证据表明，中脑回路在可卡因相关的行为。我在啮齿动物身上的初步数据表明，可卡因，而不是蔗糖，会使中脑失调。抑制电路通过降低功能的阴离子转运体，KCC2位于腹侧被盖区GABA神经元。这种形式可卡因诱导的GABA能信号传导神经适应的研究以前没有描述过，我计划研究其对大鼠可卡因自我给药的影响。鉴于我的初步调查结果显示 KCC2功能障碍有助于可卡因的动机特性，我将测量可卡因自我的动机。给药，同时操纵VTA中的KCC2活性。在细胞水平，KCC2功能障碍减弱 GABAA受体介导的抑制导致VTA GABA神经元的过度兴奋。评估的作用 VTA GABA神经元对可卡因的兴奋性，我将采用化学遗传学的方法在转基因大鼠模型中直接在可卡因自我给药期间操纵神经元活动。最后，我会测试可卡因是否会以电路特异性方式的GABA能信号传导。越来越多的证据表明腹侧被盖区GABA神经元投射到多个大脑区域，我将专注于GABA能投射到脑桥核，与成瘾药物的动机特性密切相关的区域。我将标记特定的VTA GABA投射并测试可卡因对GABA能信号传导的影响在这些预测中。总之，这项研究将阐明中脑GABA能回路在脑内的作用。可卡因的病态动机

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute Nicotine Exposure Alters Ventral Tegmental Area Inhibitory Transmission and Promotes Diazepam Consumption.

急性尼古丁暴露会改变腹侧被盖区抑制性传播并促进地西泮的消耗。

DOI：
10.1523/eneuro.0348-19.2020
发表时间：
2020
期刊：
eNeuro
影响因子：
3.4
作者：
Ostroumov,Alexey;Wittenberg,RuthieE;Kimmey,BlakeA;Taormina,MadisonB;Holden,WilliamM;McHugh,AlbertT;Dani,JohnA
通讯作者：
Dani,JohnA