权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Plasticity of GABA input to VTA dopamine neurons in opioid use disorders

阿片类药物使用障碍中 VTA 多巴胺神经元 GABA 输入的可塑性

基本信息

批准号：
10512049
负责人：
Michael J Beckstead
金额：
--
依托单位：
OKLAHOMA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2025-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512049
关键词：
Ablation Abstinence Affect Affinity Chromatography Aging Alleles Area Astrocytes Attention Behavior Behavioral Bioinformatics Brain Breeding Cell Nucleus Chest Clinical Code Cre lox recombination system Cues DNA Data Dependovirus Development Disease Disinhibition Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Family member Female Fentanyl Gene Expression General Population Genes Genetic Glean Hypothalamic structure Individual Injections Intake Knock-out Knowledge Label Lateral Link LoxP-flanked allele Maintenance Measures Mediating Molecular Mus Neurons Neurotensin Neurotensin Receptors Neurotransmitters Nociception Nuclear Nucleic Acids Nucleus Accumbens Opioid Opioid Receptor Overdose Pain Pain management Pathway interactions Peptides Pharmaceutical Preparations Physiological Procedures Property Psychological reinforcement Public Health Quality of life RNA Rattus Receptor Signaling Recording of previous events Relapse Ribosomes Risk Role Self Administration Signal Transduction Site Slice Source Suicide Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Titrations Translating Ventral Tegmental Area Veterans Viral Virus Withdrawal Work Writing adverse outcome aldehyde dehydrogenase 1 analog cell type chronic pain management designer receptors exclusively activated by designer drugs dopamine transporter dopaminergic neuron drug reinforcement epigenomics experience experimental study gamma-Aminobutyric Acid gene interaction improved innovation male mouse genetics mu opioid receptors neuronal excitability neurophysiology new therapeutic target novel opioid abuse opioid epidemic opioid exposure opioid use opioid use disorder optogenetics patch clamp prescription opioid presynaptic receptor remifentanil side effect suicidal risk tool transcriptome transcriptomics treatment strategy vesicular GABA transporter

项目摘要

Despite their dangers, the number of opioid prescriptions written for veterans has increased sharply since 2000, and veterans are more prone than the general population to both suicide and the development of use disorders following opioid treatment. Target receptors for opioids are widely expressed throughout the brain and periphery, but their reinforcing properties are largely mediated by their action in mesocorticolimbic areas such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). In the VTA, activation of presynaptic mu-opioid receptors is known to blunt release of the inhibitory neurotransmitter GABA, thus “disinhibiting” dopamine neuron activity. Preliminary work has established that the modulatory peptide neurotensin can activate presynaptic neurotensin 1 receptors (NtsR1) to enhance GABA release in the VTA. While this novel form of synaptic plasticity would be expected to directly counteract the effects of opioids, it is not known how repeated opioid exposure interacts with neurotensin effects on GABA signaling. Opioids and neurotensin are both known to modulate pain; however, there are significant gaps in our knowledge of how these compounds interact at the synaptic and circuit level in the VTA to affect drug reinforcement. Improved treatments for opioid use disorders are desperately needed, both for the general population but also for aging veterans that will increasingly develop painful conditions that require long-term treatment. The proposed studies are necessary to determine the feasibility of targeting the neurotensin system to modulate reinforcement and relapse in individuals that no longer can control their opioid intake. We will combine brain slice electrophysiology and cell type-specific molecular techniques with self- administration of the opioid remifentanil in mice to explore these issues. The use of operant self-administration in mice offers several key advantages: mice are able to titrate their intake based on individual sensitivity, and using mice instead of rats opens up the powerful tools of mouse genetics (i.e., Cre-lox technology) to experimental manipulations. The hypothesis to be tested is that a history of remifentanil self-administration decreases neurotensin-induced enhancement of GABA release in the NAc  VTA circuit, removing a critical break on dopamine neuron excitability during drug intake to increase reinforcement. Experiments in Aim 1 will identify the sensitivity of individual GABA inputs in the VTA to neurotensin, and determine how plasticity is affected by remifentanil self-administration as well as following a forced abstinence. Experiments in Aim 2 will use chemogenetics to activate specific GABA inputs to determine their effect on remifentanil self-administration behavior and cue responding following a forced abstinence. A novel cell type-specific neurotensin receptor knockout will provide additional information on the role of specific cell types on opioid self-administration. Experiments in Aim 3 will use a discovery approach to determine transcriptomic and epigenomic alterations following remifentanil self-administration in single cell types of the VTA. This will be done with several novel NuTRAP (Nuclear Tagging and Translating Ribosome Affinity Purification) mouse lines under the control of Cre recombinase that allow for labeling and isolation of both DNA and RNA from specific cell types. Improved strategies are desperately needed to improve the quality of life for veterans at risk of adverse consequences following opioid treatment. Data obtained will delineate the behavioral and physiological interactions between GABA input to the VTA, neurotensin signaling, and opioid exposure, and identify novel gene and receptor targets for exploration as treatments for opioid use disorders.

尽管存在危险，但此后为退伍军人开出的阿片类药物处方数量急剧增加