Neural mechanisms regulating cocaine consumption

调节可卡因消耗的神经机制

• 批准号: 10215470
• 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
• 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/10215470
• 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; Side; Signal Transduction; System; Testing; Training; United States; Ventral Tegmental Area; Viral; Work; base; cell type; cocaine self-administration; 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

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.

摘要