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：
10398981
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/10398981
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 Pharmacology Pharmacotherapy Physiology Play Population Property Public Health Publishing Rattus Receptor Activation Reporting Research Rewards Rodent Role Self Administration Signal Transduction Slice Substance Use Disorder Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Therapeutic Time Training Transgenic Organisms Ventral Tegmental Area Viral Volition Work addiction cell type cellular targeting cocaine exposure cocaine overdose cocaine self-administration cocaine use cost designer receptors exclusively activated by designer drugs dopaminergic neuron effective therapy experimental study gamma-Aminobutyric Acid mesolimbic system neural circuit neural repair neuroadaptation neuropsychiatric disorder novel overdose death receptor reward circuitry substance use 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主要公共卫生问题，但有效的治疗仍在缺乏。可卡因使用障碍的特征是发展可卡因的病理动机，面对成本上升和有害后果的摄入量为特征。减少过度毒品服用而无需改变自然奖励的动机重要性是主要目标之一治疗可卡因成瘾。但是，新药物治疗的开发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，因为可卡因在过去的几年中，使用和过量剂量一直在增加。越来越多的证据表明，中脑电路在与可卡因有关行为。我在啮齿动物中的初步数据表明可卡因，但不能蔗糖，使中脑失调抑制性电路通过位于VTA GABA神经元中的阴离子转运蛋白KCC2的功能降低。此形式以前尚未描述可卡因诱导的GABA能信号传导中的神经适应研究其对大鼠可卡因自我给药的影响。鉴于我的初步发现表明 KCC2功能障碍有助于可卡因的动机性能，我将衡量可卡因自我的动机在操纵VTA中的KCC2活性的同时进行给药。在细胞水平，KCC2功能障碍减弱 GABAA受体介导的抑制作用导致VTA GABA神经元过度兴奋。评估角色可卡因动机中的VTA GABA神经元，我将在转基因大鼠模型中使用化学发生方法直接可卡因自我管理过程中的神经元活性。最终，我将测试可卡因是否失调 GABA能信号以特定电路的方式传导。积累的证据表明VTA GABA神经元投影到多个大脑区域，我将专注于对伏伏核的Gabaergic投影，一个大脑区域与成瘾性药物的动机性特性有关。我将标记特定的VTA GABA预测到伏隔核的内侧和外侧壳，并测试可卡因对GABA能信号的影响在这些预测中。综上可卡因的病理动机。