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​​祉的严重且日益严重的关注，但没有FDA批准的治疗 可卡因使用障碍（CUD）的人的选项，使其成为至关重要的未满足需求。 CUD是一个复杂的 受许多外部因素（例如压力）影响的疾病。尽管压力很普遍 在整个人群中，包括患有CUD的人，大多数临床前成瘾研究都不 检查药物摄入过程中压力的影响。了解压力和药物摄入如何与 影响行为和神经生物学结果，我们开发了可卡因自我管理的大鼠模型 （SA）在大鼠可卡因自我给药时结合了重复的压力。该模型导致 可卡因摄入量的升级在原本稳定的反应大鼠中，可卡因的持久增强 寻求行为。我们建议这种行为转移受内源性大麻素（ECB）的变化调节 系统，唯一地调节压力和奖励系统。为此，全身管理 大麻素受体1（CB1R）拮抗剂仅在患有病史的大鼠中可卡因诱导的可卡因诱导的恢复原状 压力。此外，我的初步数据将此效果定位于预宾皮质（PLC），这是一个关键站点 调节压力和寻求毒品行为。重要的是，通过局部衰减，欧洲央行信号传导 抑制性神经传递良好，以调节PLC锥体神经活性和输出。一个这样的 PLC输出是对伏隔核（NACC）的，该核心已证明可以调节可卡因寻求可卡因 行为。因此，该提案检验了以下假设，即应力和可卡因诱发的欧洲央行变化 可卡因SA期间的信号传导允许通过对NACC电路的DISIS抑制可卡因寻求可卡因。 首先，该提案将使用PLC定向的CB1R药物操纵来评估欧洲央行的作用 对可卡因SA和/或重复应力史的大鼠可卡因剂恢复的信号传导。下一个， 我们将使用体内纤维光度法来记录可卡因过程中PLC→NACC电路的活性 恢复有压力史或没有压力的大鼠。这将使我们能够衡量个人或 可卡因SA病史和/或反复压力对可卡因的行为的结合影响。最后，使用 原位杂交，我们将研究可卡因SA和/或反复的压力如何在长期变化中 分子机械调节PLC→NACC电路处的欧洲央行信号传导。这些研究将扩大我们的 了解压力 - 药水相互作用，并可能会在患有CUD的个体中产生新的治疗选择 压力是主要的促成因素。