Mechanistic studies of cAMP effectors in cocaine addiction

cAMP效应子在可卡因成瘾中的机制研究

基本信息

批准号：
10646409
负责人：
Qing-song Liu
金额：
$ 35.42万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646409
关键词：
Abstinence Action Potentials Addictive Behavior Address Affect Attenuated Behavior Behavioral Brain region CREB1 gene Co-Immunoprecipitations Cocaine Cocaine Dependence Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotides Dopamine Drug Addiction Drug Regulations Drug abuse Drug usage Economic Burden Electrophysiology (science)Exocytosis Exposure to FDA approved Face Funding Goals Grant Incubated Injections Intraperitoneal Injections Knock-out Knowledge Lateral Learning Maintenance Mediating Medical Microinjections Modeling Motivation Mus Neurons Nucleus Accumbens Periodicity Permeability Pharmaceutical Preparations Proteins Psychological reinforcement Publishing Rattus Role Scanning Schedule Self Administration Signal Pathway Signal Transduction Synapses Synaptic plasticity Testing United States National Institutes of Health Up-Regulation Ventral Tegmental Area Viral Work abuse liability addiction antagonist cell type cocaine craving cocaine self-administration conditional knockout conditioned place preference cyclic-nucleotide gated ion channels dopaminergic neuron drug of abuse drug reinforcement inhibitor ivabradine knock-down mesolimbic system neuroadaptation postsynaptic presynaptic rab3 GTP-Binding Proteins small hairpin RNA success transmission process

项目摘要

Project Summary Cocaine addiction is a substantial medical and economic burden in the U.S. and worldwide. There currently are no FDA-approved medications for treating cocaine addiction. Repeated exposure to drugs of abuse including cocaine induces the upregulation of cAMP-dependent signaling in the mesolimbic system that initiates the transition to addiction. cAMP has three direct effectors: protein kinase A (PKA), exchange proteins activated by cAMP (Epac), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Much work has been done to characterize the cAMP-PKA signaling pathway in the regulation of drug reinforcement and addictive behavior. However, few studies have addressed how the “other” cAMP effectors regulate the cellular and behavioral effects of drugs of abuse. During our prior NIH funding period, we provided the first evidence for Epac2-mediated modulation of cocaine-induced excitatory and inhibitory synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) and conditioned place preference. Drug self- administration has a high degree of face and predictive validity for abuse liability and is the gold standard for studying the reinforcing effects of drugs of abuse. However, whether and how Epac regulates cocaine self- administration remains unknown. Building on work from our previously funded grant period and our preliminary studies, the long-term goal of this R01 renewal is to test the hypothesis that Epac and HCN act via distinct but complementary mechanisms to regulate dopaminergic transmission and cocaine-induced long-term plasticity, and that these mechanisms contribute to cocaine reinforcement and seeking behavior. Using viral-mediated knockdown, conditional knockouts, fast-scan cyclic voltammetry (FSCV), electrophysiology, and cocaine self- administration, we will test this hypothesis via three Specific Aims. In Aims I and II, we will unravel the region- and cell type-specific mechanisms whereby Epac2 in the VTA and nucleus accumbens contribute to cocaine reinforcement and seeking behavior, respectively. In Aim III, we will determine how cocaine self-administration- induced, cAMP-mediated adaptations in HCN2 channels in VTA dopamine neurons contribute to cocaine reinforcement. These detailed, mechanistic studies are expected to provide first evidence that these under- studied cAMP effectors in the mesolimbic dopamine system regulate reinforced cocaine self-administration and drug seeking.

项目摘要可卡因成瘾是美国和世界范围内的大量医疗和经济伯恩。那里目前尚无对可卡因成瘾治疗可卡因成瘾的药物。反复接触药物包括可卡因在内启动过渡到成瘾。 CAMP具有三个直接影响：蛋白激酶A（PKA），交换蛋白质被CAMP（EPAC）激活和超极化激活的循环核苷酸门控通道。很多已经完成了在药物加固调节中表征CAMP-PKA信号通路的工作和加性行为。但是，很少有研究解决了“其他”营地效应如何调节滥用药物的细胞和行为影响。在以前的NIH资金期间，我们提供了第一个 EPAC2介导的可卡因引起的兴奋和抑制性合成可塑性的调节的证据腹侧对盖区（VTA）和条件位置偏好的多巴胺神经元。毒管理对虐待责任具有高度的面部和预测有效性，是黄金标准研究滥用药物的增强作用。但是，EPAC是否以及如何调节可卡因自我管理仍然未知。基于我们以前资助的赠款期和我们的初步的工作研究，该R01更新的长期目标是检验EPAC和HCN通过不同但完全调节多巴胺能传播和可卡因诱导的长期可塑性的机制，这些机制有助于可卡因加强和寻求行为。使用病毒介导敲低，有条件的敲除，快速扫描循环伏安法（FSCV），电生理学和可卡因自我管理，我们将通过三个特定目标检验这一假设。在目标I和II中，我们将揭示该地区 - 和细胞类型特异性的机制，VTA中的EPAC2和伏隔核有助于可卡因分别加强和寻求行为。在AIM III中，我们将确定可卡因如何自我管理 - VTA多巴胺神经元中HCN2通道中诱导的，cAMP介导的适应性促成可卡因加强。这些详细的机械研究有望提供首先证据，证明这些研究低于中唇胺多巴胺系统中的训练营效应调节可卡因自我管理和寻求毒品。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Application of optogenetics and in vivo imaging approaches for elucidating the neurobiology of addiction.

DOI：
10.1038/s41380-021-01181-3
发表时间：
2022-01
期刊：
MOLECULAR PSYCHIATRY
影响因子：
11
作者：
Vickstrom, Casey R.;Snarrenberg, Shana Terai;Friedman, Vladislav;Liu, Qing-song
通讯作者：
Liu, Qing-song

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement.

DOI：
10.1038/s41380-023-02290-x
发表时间：
2023-09
期刊：
MOLECULAR PSYCHIATRY
影响因子：
11
作者：
Mu, Lianwei;Liu, Xiaojie;Yu, Hao;Vickstrom, Casey R.;Friedman, Vladislav;Kelly, Thomas J.;Hu, Ying;Su, Wantang;Liu, Shuai;Mantsch, John R.;Liu, Qing-song
通讯作者：
Liu, Qing-song

Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum.

DOI：
10.1523/eneuro.0048-16.2016
发表时间：
2016-05
期刊：
eNeuro
影响因子：
3.4
作者：
Chen Y;Liu X;Vickstrom CR;Liu MJ;Zhao L;Viader A;Cravatt BF;Liu QS
通讯作者：
Liu QS

The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson's Disease.

DOI：
10.3390/cells10123548
发表时间：
2021-12-16
期刊：
Cells
影响因子：
6
作者：
Yu H;Liu X;Chen B;Vickstrom CR;Friedman V;Kelly TJ;Bai X;Zhao L;Hillard CJ;Liu QS
通讯作者：
Liu QS

Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.