5-HT7 receptor modulation of cocaine effects

5-HT7 受体调节可卡因作用

基本信息

批准号：
10669301
负责人：
M. FOSTER OLIVE
金额：
$ 7.2万
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/10669301
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 Modulation Drug Receptors 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 Medicine Memory Mental Depression Mental disorders Modeling Motivation Neuroanatomy Neuronal Plasticity Neurotransmitters Nicotine Opioid Pattern Pharmaceutical Preparations Pharmacological Treatment Phenotype Pre-Clinical Model Price Procedures Process Productivity Property Psychological reinforcement Rattus Receptor Activation 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 Universities addiction alcohol involvement alcohol use disorder antagonist behavioral economic analysis behavioral economics brain circuitry cocaine overdose cocaine seeking cocaine self-administration cocaine use comorbidity consumption measures cost cost estimate male mathematical model monoamine neural novel pharmacologic pre-clinical research protein expression receptor response serotonin 7 receptor success translational potential

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.

概括对于可卡因使用障碍（CUD），目前仍然没有广泛接受的药物治疗方法过去十年来，可卡因吸食和过量服用有所增加。可卡因的精神作用主要是由于单胺神经递质的增强和延长作用，包括血清素（5- HT）。在5HT激活的受体中，5-HT7受体（5-HT7R）在多种神经系统中发挥作用。 CUD 涉及的过程，包括学习和记忆、神经可塑性、睡眠、冲动和寻求感觉。这些受体还调节临床前模型和 5-HT7R 中的酒精摄入量多态性与酒精使用障碍有关。因此，令人惊讶的是 5-HT7Rs 在 CUD 相关行为尚未得到探索。我们在雄性大鼠中的初步数据表明 5-HT7R 激动剂和拮抗剂药物调节可卡因自我给药，拮抗剂减少可卡因寻求行为。我们假设 5-HT7R 拮抗剂抑制可卡因，而 5-HT7R 激动剂增强可卡因可卡因的强化和动机。我们将在给予延长时间的雄性和雌性大鼠中测试这一假设每天获取可卡因以建立成瘾表型。然后我们将测试 5-HT7R 拮抗剂的效果， MC-RG19 和激动剂 AS-19 通过疗程内剂量减少进行可卡因自我给药大鼠可接触 9 种不同剂量的可卡因，每种剂量 10 分钟，按剂量递减顺序专注。根据结果生成的需求曲线的行为经济学分析将用于估计需求强度和需求弹性，这被认为反映了强化和激励可卡因的特性。我们还将检查 5-HT7R 药物对可卡因诱导的影响基因表达的变化，使用 Fos 蛋白的免疫组织化学作为这些变化的标记。我们预期拮抗剂会降低需求强度并增加需求弹性，而激动剂会降低需求强度并增加需求弹性会产生相反的效果。可卡因诱导的 Fos 表达的类似变化模式是预期发生在参与 CUD 的中皮质边缘大脑区域。该项目将是第一个描述 5-HT7R 在可卡因自我给药中的作用。如果我们的预测成立，结果将表明 5-HT7R 拮抗剂可能可作为治疗 CUD 的新药物。特定地区的变化 Fos 表达将揭示 5-HT7R 药物作用所涉及的神经解剖学机制可卡因自我给药。