Neural mechanisms regulating cocaine consumption

调节可卡因消耗的神经机制

基本信息

批准号：
10035032
负责人：
Paul E. M. Phillips
金额：
$ 51.69万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10035032
关键词：
Address Animals Attenuated Bilateral Biochemical CREB1 gene CRF receptor type 1 CRISPR/Cas technology Chronic Cocaine Cocaine Abuse Collection Consumption Contralateral Corticotropin-Releasing Hormone Dopamine Drug Regulations Drug usage Dynorphins Female Genes Glean Hour Individual Intake Intravenous Investigation Ipsilateral Modeling Neurons Nucleus Accumbens Opioid Antagonist Pathway interactions Pharmaceutical Preparations Pharmacology Phase Public Health Rattus Receptor Signaling Regulation Research Resolution Self Administration Side Signal Transduction System Testing Training United States Ventral Tegmental Area Viral Work base cell type cocaine use design dopaminergic neuron experimental study insight kappa opioid receptors knock-down male neural circuit neurochemistry neuromechanism neuroregulation overdose death overdose risk relating to nervous system substance abuser tool transcription factor transmission process

项目摘要

Abstract Cocaine abuse remains a major burden on public health with significant numbers of overdose deaths each year. The proposed work characterizes a neural circuit that underlies the increased drug consumption that takes place by some individuals following chronic drug use. This application leverages previous work demonstrating that corticotropin releasing factor (CRF), dynorphin and dopamine signaling can individually impact drug intake and that each of these systems changes with chronic cocaine use. Specifically, the proposed experiments ask how these three neuromodulatory systems interact with each other in the regulation drug consumption. The working hypothesis is that escalation of drug intake following chronic drug use, comes about through a serial pathway where elevated CRF levels causes an increase in dynorphin which consequently reduces dopamine release, producing escalation. However, the experiments are designed to systematically test the functional connections between each of these nodes in the regulation of cocaine intake and, in doing so, discern between eight competing models of the interactions. Therefore, regardless, of whether the results match the working hypothesis or not, the experiments will yield new insight into the interactions between these systems. This information will inform potential treatment targets for moderating intake in substance abusers and thereby reducing harm.

抽象的可卡因滥用仍然是公共卫生的主要负担，导致大量吸毒过量死亡每年。拟议的工作描述了增加药物背后的神经回路一些人在长期吸毒后发生的消费。该应用程序利用先前的工作证明促肾上腺皮质激素释放因子（CRF）、强啡肽和多巴胺信号传导可以单独影响药物摄入，并且这些系统中的每一个都会随着慢性病的发生而变化使用可卡因。具体来说，拟议的实验询问这三种神经调节系统如何药物消费的调节相互作用。工作假设是升级慢性吸毒后的药物摄入量是通过一系列途径产生的，其中 CRF 升高水平导致强啡肽增加，从而减少多巴胺释放，产生升级。然而，实验旨在系统地测试功能连接在可卡因摄入调节中的每个节点之间进行区分，并在此过程中区分八个相互作用的竞争模型。因此，无论结果是否与工作相符无论是否有假设，这些实验都将对这些系统之间的相互作用产生新的见解。这些信息将为控制药物滥用者的摄入量提供潜在的治疗目标和从而减少伤害。