Cocaine-motivated behaviors: development of novel viral-based strategies to target orexinergic input to the infralimbic cortex.

总结 尽管科学界做出了相当大的努力来发现可卡因使用障碍的有效治疗方法， 实现戒断和防止复发仍然是严峻的挑战。orexin（orx）系统 与动机、唤醒和压力的调节有关，使这个系统成为一个 理想的治疗目标。CONDITION导致Orx系统发生不适应的变化， 反过来又可能维持可卡因的摄入并促进复吸。我们的研究表明敲门 下调下丘脑中的Orx基因减弱了可卡因的自我给药 而Orx神经元在可卡因寻求过程中被强烈招募。特别是，奖励 寻找主要与外侧下丘脑中Orx细胞的募集有关 （LH）. Orx系统已被证明在介导几种药物的作用中起作用， 滥用，包括可卡因，通过投射到关键的大脑区域，如前额叶皮层。 食欲素神经元密集地投射到边缘下皮层（IL）。IL主要与 在反应抑制，并被称为衰减依赖于可卡因相关的行为， 记忆，如线索诱导的恢复。然而，有相互矛盾的证据表明， IL在可卡因寻求中的作用及其在可卡因动机行为的另一个方面，即 可卡因自我给药，只是最近才开始调查。有争议的数据 可卡因条件性复吸和可卡因自我给药的有限数据， 阻碍了我们对IL参与抑制或促进 可卡因激发的行为（例如，摄入和复发）。此外， 使IL抑制或促进可卡因动机的行为仍然是未知的。考虑 IL在反应抑制中的作用和LH Orx在奖赏寻求中的作用，我们假设， LH Orx输入IL的活动将通过抑制 对可卡因摄入的动机和预防可卡因复吸和可卡因滥用 干扰并扰乱了这个电路。本项目将调查LH Orx的贡献 在可卡因成瘾周期的两个不同方面对IL的预测：摄入和复发。 该项目将使用新的病毒载体，表达一种设计受体， 可以选择性靶向大鼠Orx神经元亚群的设计药物（DREADD）：ORX- LV-hM3D（Gq）和ORX-LV-hM4D（Gi）。使用这些DREADD，我们将测试 操纵（激活或抑制）LH Orx向IL的输入干扰可卡因摄入， 线索诱导的复职该提案将提供有关特定 LH [Orx]® IL回路参与可卡因动机行为的神经生物学。

SUMMARY Despite considerable scientific efforts to discover effective treatments for cocaine use disorder, achieving abstinence and preventing relapse remain serious challenges. The orexin (Orx) system has been implicated in the regulation of motivation, arousal, and stress, making this system an ideal target for addiction treatment. Cocaine causes maladaptive changes in the Orx system that in turn might maintain cocaine intake and promote relapse. Our research has shown that knocking down the Orx gene in the hypothalamus attenuates extended-access cocaine self-administration in rats and that Orx neurons are strongly recruited during cocaine seeking. In particular, reward seeking has been primarily associated with the recruitment of Orx cells in the lateral hypothalamus (LH). The Orx system has been shown to play a role in mediating the effects of several drugs of abuse, including cocaine, via projections to key brain regions, such as the prefrontal cortex. Orexin neurons project densely to the infralimbic cortex (IL). The IL has been primarily implicated in response inhibition and is known to attenuate behaviors that depend on cocaine-related memories, such as cue-induced reinstatement. However, there is conflicting evidence of the role of the IL in cocaine seeking and its role in another aspect of cocaine-motivated behaviors, namely cocaine self-administration, has only recently begun to be investigated. The controversial data on cocaine conditioned reinstatement and the limited data on cocaine self-administration have hampered our understanding of the way in which the IL is involved in suppressing or promoting cocaine-motivated behaviors (e.g., intake and relapse). Moreover, the precise mechanisms that enable the IL to inhibit or facilitate cocaine-motivated behaviors are still unknown. Considering the function of the IL in response inhibition and LH Orx in reward seeking, we hypothesize that the activity of LH Orx inputs to the IL will influence reward-motivated behaviors by suppressing motivation toward cocaine intake and preventing cocaine relapse and that cocaine abuse engages and perturbs this circuitry. The present project will investigate the contribution of LH Orx projections to the IL in two different aspects of the cocaine addiction cycle: intake and relapse. This project will use new viral vectors that express a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) that can selectively target subpopulation of Orx neurons in rats: ORX- LV-hM3D(Gq) and ORX-LV-hM4D(Gi). Using these DREADDs, we will test whether the manipulation (activation or inhibition) of LH Orx inputs to the IL interferes with cocaine intake and cue-induced reinstatement. This proposal will provide unique information about the specific involvement of the LH[Orx]®IL circuit in the neurobiology of cocaine-motivated behaviors.