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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：
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.

在美国，可卡因成瘾仍然是一个主要的公共卫生问题，但有效的治疗方法仍然存在