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Cholinergic mechanisms of cocaine reinforcement probed with nicotinic receptor gene editing

通过烟碱受体基因编辑探讨可卡因强化的胆碱能机制

基本信息

批准号：
10705090
负责人：
Ryan Michael Drenan
金额：
$ 19.38万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705090
关键词：
Acute Anatomy Automobile Driving Behavior Behavioral Behavioral Assay Behavioral Genetics Biological Models Brain Cells Cellular Assay Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Abuse Cocaine Dependence Cocaine Users Cocaine use disorder Coupled Data Detection Development Dopamine Dose Economics Electrophysiology (science)Female Fiber Fostering Funding Genes Genetic Polymorphism Genome Goals Health Individual Intake Intravenous Investigation Kinetics Knock-out Knowledge Laser Scanning Microscopy Learning Link Location Mediating Methods Modeling Molecular Motivation Neurons Neuropharmacology Nicotinic Receptors Optical Methods Outcome Pharmaceutical Preparations Pharmacology Phase Phenotype Photometry Physiology Play Psychological reinforcement Public Health Qualifying Rattus Receptor Activation Receptor Cell Receptor Gene Research Rewards Risk Rodent Role Self Administration Signal Transduction Slice Smoke Substance Use Disorder Testing Therapeutic Tissues Tobacco Tobacco Dependence Tobacco use Up-Regulation Validation Variant Ventral Tegmental Area Work adeno-associated viral vector attenuation behavioral pharmacology biophysical techniques cell type cholinergic cigarette smoking cocaine exposure cocaine self-administration cocaine use comorbidity experimental study gain of function gamma-Aminobutyric Acid genome editing genome wide association study improved in vivo innovation insight knock-down male neurobiological mechanism nicotinic receptor beta2 non-smoker novel novel strategies optogenetics patch clamp pre-clinical programs receptor function response success tool treatment strategy two-photon

项目摘要

PROJECT SUMMARY Cocaine use disorder represents a major public health challenge, and novel treatment approaches are urgently needed. Tobacco usage is highly co-morbid with cocaine use disorder, and at present, it is not known whether/how nicotinic signal transduction modulates the brain's response to cocaine. We hypothesize that tobacco usage contributes to cocaine use, and we will model this research question using a rat model system. We will probe the mechanistic underpinnings of nicotinic modulation of cocaine reinforcement, focusing on identifying key nicotine receptors and nerve cell types in the brain's reward circuit. In the R21 phase, we will validate a set of molecular tools that we developed in a previously funded project. These tools allow us to reduce or eliminate the expression of specific nicotine receptors in precise cell types in the brain. We'll verify that these tools work for their purpose in this project, examining how well they reduce nicotine receptor function in cellular assays (Aim 1). This involves single-cell patch-clamp recordings and fiber photometry. In R21 Aim 2, we will determine whether/how nicotine receptor functional attenuation impacts cocaine self-administration behavior. Specific manipulations that impact cocaine reinforcement will be confirmed with replication studies and other control experiments then advanced to the R33 phase for further investigation. In the R33, we will further probe the mechanisms by which nicotine receptors modulate cocaine reinforcement. R33 Aim 3 will probe the circuits involved in nicotine receptor modulation of cocaine self-administration. R33 Aim 4 will use a biophysical approach to examine the novel hypothesis that cocaine has direct acute and long-term interactions with nicotine receptors. Together, these AIMs will help us understand how nicotine receptor activity modulates cocaine intake. Associated neurobiological mechanisms will be identified, potentially leading to novel approaches to treat tobacco and/or cocaine dependence.

项目总结