5-HT7 receptor modulation of cocaine effects

5-HT7 受体调节可卡因作用

• 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
• 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

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 仍然没有可卡因使用障碍（CUD）的广泛接受的药理疗法，而 在过去的十年中，可卡因的使用和过量服用都在增加。可卡因的心理活性 主要是由于单胺神经递质（包括5-羟色胺）的增强和延长作用（5-- HT）。在5HT激活的受体中，5-HT7受体（5-HT7R）在几个神经中起作用 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-HT7R在 尚未探讨与CUD相关的行为。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，拮抗剂会降低可卡因 - 寻求行为。我们假设5-HT7R拮抗剂抑制了，而5-HT7R激动剂可以增强可卡因 可卡因的增强和动机。我们将在延长的男性和雌性大鼠中检验该假设 每天访问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，使用会话内部降低剂量的可卡因自我管理 步骤，使大鼠可以使用9种不同剂量的可卡因，每个可卡因10分钟以降序的顺序 专注。对结果产生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，这被认为反映了增强和激励性的 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志。我们 预计对手会降低需求强度并增加需求弹性，而动力学家 将产生相反的效果模式。可卡因诱导的FOS表达的类似模式是 涉及CUD的中质粒细胞脑区域中的预期。这个项目将是第一个 表征5-HT7R在可卡因自我管理中的作用。如果我们的预测得到了维持，结果将 表明5-HT7R拮抗剂可能可作为CUD的新药物有用。区域特定的变化 FOS表达将阐明5-HT7R药物对5-HT7R药物影响的神经解剖机制 可卡因自我管理。

项目成果

Influence of gut microbiome metabolites on cocaine demand and cocaine-seeking behavior.

肠道微生物代谢物对可卡因需求和可卡因寻求行为的影响。

• DOI: 10.1038/s41386-023-01743-9
• 发表时间: 2024
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Acuña,AmandaM;Olive,MFoster
• 通讯作者: Olive,MFoster