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

项目摘要 可卡因的使用是一个严重的和日益增长的关注公众福祉，但没有FDA批准的治疗 可卡因使用障碍（CUD）患者的选择，使其成为一个关键的未满足的需求。CUD是一种复杂的 受许多外部因素影响的疾病，如压力。尽管压力很大 在整个人群中，包括CUD患者，大多数临床前成瘾研究都没有 研究药物摄入过程中压力的影响。为了了解压力和药物摄入如何相互作用， 影响行为和神经生物学结果，我们开发了一种可卡因自我给药的大鼠模型， (SA)这是在老鼠自我注射可卡因时反复出现的压力。这种模式导致了 在其他方面稳定的反应大鼠中可卡因摄入量的增加和可卡因的持久增强- 寻求行为。我们认为，这种行为转变是由内源性大麻素（eCB）的变化调节的。 系统，它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（CB 1 R）拮抗剂仅在有病史的大鼠中减弱可卡因诱导的复吸 压力此外，我的初步数据将这种效应定位于前边缘皮层（PLc），这是一个关键部位， 调节压力和寻求药物的行为。重要的是，eCB信号传导，通过减弱局部 抑制性神经传递，很好地定位于调节PLc锥体神经元活性和输出。一个这样 PLc的输出是到丘脑核（NAcc），这已被证明是调节可卡因寻求 行为因此，该提案测试了压力和可卡因诱发的eCB变化的假设， 可卡因SA期间的信号传导允许通过PLc到NAcc回路的去抑制来增强可卡因寻求。 首先，该提案将使用PLC指导的CB 1 R药理学操作来评估eCB的作用 在可卡因引发的恢复与可卡因SA和/或反复应激史的大鼠的信号。下一个是 我们将使用体内纤维光度法记录可卡因引发期间PLc→NAcc回路的活动 在有应激史或无应激史的大鼠中恢复。这将使我们能够衡量个人或 可卡因SA史和/或反复应激对可卡因寻求行为的综合影响。最后利用 在原位杂交，我们将研究如何可卡因SA和/或重复的压力产生长期的变化， 在PLc→NAcc回路中调节eCB信号传导的分子机制。这些研究将扩大我们的 了解压力-药物相互作用，并可能为CUD患者提供新的治疗选择， 压力是主要的影响因素。

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.