Endocannabinoid regulation of the corticoaccumbens pathway and stress-enhanced cocaine-seeking behavior

内源性大麻素对伏隔皮质通路的调节和压力增强的可卡因寻求行为

• 批准号: 10750394
• 负责人: Andrew Gaulden
• 金额: $ 4.51万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-09 至 2026-08-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750394
• 关键词: Abstinence; Acute; Affect; American; Area; Attenuated; Behavior; Behavioral; Behavioral Model; Brain; CNR1 gene; Cocaine; Cocaine use disorder; Complex; Corticosterone; Data; Dedications; Disease; Disinhibition; Drug Interactions; Endocannabinoids; FDA approved; Fiber; Goals; Health; Human; In Situ Hybridization; Individual; Intake; Interneurons; Knowledge; Measurement; Measures; Mediating; Modeling; Molecular; Neurobiology; Neurons; Neurotransmitters; Nucleus Accumbens; Outcome; Output; Pathologic; Pathway interactions; Pattern; Personal Satisfaction; Pharmaceutical Preparations; Photometry; Population; Positioning Attribute; Prefrontal Cortex; Prevalence; Rattus; Recording of previous events; Regulation; Research; Research Personnel; Rewards; Rodent; Role; Self Administration; Signal Transduction; Site; Stimulus; Stress; Substance Use Disorder; System; Testing; Time; addiction; antagonist; attenuation; behavior influence; cell type; cocaine craving; cocaine seeking; cocaine self-administration; cocaine use; drug seeking behavior; endocannabinoid signaling; endogenous cannabinoid system; experimental study; hippocampal pyramidal neuron; in vivo; innovation; insight; neuroadaptation; neurophysiology; neuroregulation; neurotransmission; pharmacologic; pre-clinical; skills; stressor

Project Summary Cocaine use is a serious and growing concern for public wellbeing, yet there is no FDA-approved treatment option for individuals with cocaine use disorder (CUD), making it a critical unmet need. CUD is a complex disorder that is influenced by many external factors, such as stress. Despite the prevalence of stress throughout human populations, including individuals with CUD, most pre-clinical addiction research does not examine the impact of stress during drug intake. To understand how stress and drug intake interact to influence behavioral and neurobiological outcomes, we developed a rat model of cocaine self-administration (SA) that combines repeated stress at the time of cocaine self-administration in rats. This model causes an escalation of cocaine intake in otherwise stable responding rats and a long-lasting enhancement of cocaine- seeking behavior. We propose that this behavioral shift is regulated by changes in the endocannabinoid (eCB) system, which uniquely regulates stress and reward systems. In support of this, systemic administration of a cannabinoid receptor 1 (CB1R) antagonist attenuates cocaine-induced reinstatement only in rats with a history of stress. Furthermore, my preliminary data localizes this effect to the prelimbic cortex (PLc), a key site for regulation of stress and drug-seeking behavior. Importantly, eCB signaling, through attenuation of local inhibitory neurotransmission, is well-positioned to regulate PLc pyramidal neuron activity and output. One such PLc output is to the nucleus accumbens core (NAcc), which has been shown to regulate cocaine-seeking behavior. Therefore, this proposal tests the hypothesis that stress and cocaine-evoked changes in eCB signaling during cocaine SA permits enhanced cocaine seeking via disinhibition of the PLc to NAcc circuit. First, this proposal will use PLc-directed CB1R pharmacological manipulation to assess the role of eCB signaling in cocaine-primed reinstatement for rats with a history of cocaine SA and/or repeated stress. Next, we will use in vivo fiber photometry to record activity of the PLc→NAcc circuit during cocaine-primed reinstatement in rats with a history of stress or no stress. This will allow us to measure the individual or combined impact of a history of cocaine SA and/or repeated stress on cocaine-seeking behavior. Finally, using in situ hybridization, we will examine how cocaine SA and/or repeated stress produce long-term changes in the molecular machinery regulating eCB signaling at the PLc→NAcc circuit. These studies will expand our knowledge of stress-drug interactions and may yield new treatment options in individuals with CUD for whom stress is a predominant contributing factor.

项目摘要 可卡因的使用是公众福祉的一个严重且日益严重的问题，但目前还没有FDA批准的治疗方法 可卡因使用障碍(CUD)患者的选择，使其成为一个严重的未得到满足的需求。CUD是一个复杂的 受许多外部因素影响的紊乱，如压力。尽管压力普遍存在 在整个人类群体中，包括患有CUD的个人，大多数临床前成瘾研究并不 检查吸食药物期间压力的影响。了解压力和药物摄入是如何相互作用的 影响行为和神经生物学结果，我们建立了可卡因自我给药的大鼠模型 (Sa)在大鼠体内注射可卡因时结合反复应激的情况。此模型会导致 在其他稳定反应的大鼠中，可卡因摄入量的增加和可卡因的长期增加- 寻求行为。我们认为，这种行为变化是由内源性大麻素(ECB)的变化调节的。 系统，该系统独特地调节压力和奖励系统。为了支持这一点，系统地管理 大麻素受体1(CB1R)拮抗剂仅在有病史的大鼠中减弱可卡因诱导的恢复 压力的影响。此外，我的初步数据将这种影响定位于前脑皮质(PLC)，这是 压力和寻求毒品行为的调节。重要的是，欧洲央行通过本地信号的衰减 抑制性神经传递，是很好地调节PLC锥体神经元的活动和输出。这样的一个 PLC输出到伏隔核核(NAcc)，它已被证明调节可卡因寻找 行为。因此，这一提议检验了压力和可卡因引起的欧洲央行变化的假设 可卡因SA过程中的信号允许通过解除对PLC到NAcc电路的抑制来增强可卡因寻找。 首先，该提案将使用PLC指导的CB1R药理学操作来评估ECB的作用 有可卡因SA和/或反复应激病史的大鼠在可卡因诱导的恢复中的信号传递。下一首, 我们将使用体内纤维光度法来记录可卡因激发过程中PLC→NAcc电路的活动 在有应激史或无应激史的大鼠中恢复。这将使我们能够测量个体或 可卡因吸毒史和/或反复应激对寻求可卡因行为的综合影响。最后，使用 原位杂交，我们将研究可卡因SA和/或重复应激如何产生长期变化 在可编程控制器→NAcc电路上调节欧洲央行信号的分子机制。这些研究将扩大我们的 了解应激与药物的相互作用，并可能为患有CUD的患者提供新的治疗选择 压力是主要的致病因素。