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5-HT7 receptor modulation of cocaine effects

5-HT7 受体调节可卡因效应

基本信息

批准号：
10353264
负责人：
M. FOSTER OLIVE
金额：
$ 7.25万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
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：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353264
关键词：
Abstinence Accidents Agonist Alcohol consumption Alcohol withdrawal syndrome Anxiety Behavior Brain Brain region Clinical Trials Cocaine Cocaine use disorder Collaborations Consumption Crime Cues Data Development Dose Drug Antagonism Economic Burden Elasticity Esthesia FOS Protein Family Female Gene Expression Genetic Polymorphism HTR2A gene Harvest Immunohistochemistry Impulsivity Individual Injections Investigation Irritable Bowel Syndrome Label Laboratories Learning Lifestyle-related condition Light Link Measures Memory Mental Depression Mental disorders Modeling Motivation Neuronal Plasticity Neurotransmitters Nicotine Opioid Pattern Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phenotype Play Pre-Clinical Model Price Procedures Process Productivity Property Psychological reinforcement Rattus Recording of previous events Research Role Serotonin Serotonin Receptor 5-HT1B Serotonin Receptor 5-HT2C Sleep Societies Substance Use Disorder Symptoms Testing Time Training Translating Translations Universities addiction alcohol involvement alcohol use disorder antagonist base behavioral economic analysis behavioral economics brain circuitry cocaine overdose cocaine self-administration cocaine use comorbidity consumption measures cost cost estimate male mathematical model monoamine novel pre-clinical research protein expression receptor relating to nervous system response serotonin 7 receptor success

项目摘要

Summary There is still no widely accepted pharmacological therapy available for cocaine use disorders (CUDs) while over the past decade there has been a rise in cocaine use and overdoses. The psychoactive effects of cocaine are primarily due to enhanced and prolonged actions of monoamine neurotransmitters, including serotonin (5- HT). Among the receptors activated by 5HT, the 5-HT7 receptor (5-HT7R) plays a role in several neural processes involved in CUDs, including learning and memory, neural plasticity, sleep, impulsivity, and sensation-seeking. These receptors also modulate alcohol intake in preclinical models and 5-HT7R polymorphisms have been linked to alcohol use disorders. It is therefore surprising that the role of 5-HT7Rs in CUDs-related behaviors has not yet been explored. Our preliminary data in male rats suggests that 5-HT7R agonist and antagonist drugs modulate cocaine self-administration and that the antagonist decreases cocaine- seeking behavior. We hypothesize that 5-HT7R antagonists inhibit, whereas 5-HT7R agonists enhance, cocaine reinforcement and motivation for cocaine. We will test this hypothesis in male and female rats given extended access to cocaine daily to establish an addiction phenotype. We will then test effects of a 5-HT7R antagonist, MC-RG19, and an agonist, AS-19, on cocaine self-administration using a within-session, dose-reduction procedure whereby rats have access to 9 different doses of cocaine for 10 min each in descending order of concentration. A behavioral economics analysis of demand curves generated from the results will be used to estimate demand intensity and demand elasticity, which are thought to reflect the reinforcing and motivational properties of cocaine, respectively. We will also examine effects of the 5-HT7R drugs on cocaine-induced changes in gene expression, using immunohistochemistry of Fos protein as a marker of these changes. We expect that the antagonist will decrease demand intensity and increase demand elasticity, whereas the agonist will produce the opposite pattern of effects. A similar pattern of changes in cocaine-induced Fos expression is expected in mesocorticolimbic brain regions that are involved in CUDs. This project will be the first to characterize the role of 5-HT7Rs in cocaine self-administration. If our predictions are upheld, the results will suggest that 5-HT7R antagonists may be useful as novel medications for CUDs. Region-specific changes in Fos expression will shed light on the neuroanatomical mechanisms involved in the 5-HT7R drug effects on cocaine self-administration.

总结