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

可卡因驱动的行为：开发基于病毒的新型策略，将食欲素输入瞄准边缘下皮层。

• 批准号: 10447503
• 负责人: Remi Martin-Fardon
• 金额: $ 28.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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/10447503
• 关键词: Abstinence; Affect; Anatomy; Applications Grants; Arousal; Attenuated; Behavior; Brain region; Cells; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine misuse; Cocaine use disorder; Conflict (Psychology); Cues; Data; Development; Drug usage; Eating; Electrophysiology (science); Emotional; Food; Genes; Goals; Hypothalamic structure; Intake; Lateral; Mediating; Memory; Milk; Motivation; Neurobiology; Neurons; Palate; Pharmaceutical Preparations; Physiological; Play; Prefrontal Cortex; Rattus; Regulation; Relapse; Research; Rewards; Role; Self Administration; Stimulus; Stress; System; Testing; Transgenic Organisms; Viral; Viral Vector; addiction; base; cocaine relapse; cocaine self-administration; cocaine use; designer receptors exclusively activated by designer drugs; drug of abuse; effective therapy; global health; hypocretin; improved; innovation; knock-down; motivated behavior; novel; prevent; receptor; recruit; response; therapeutic target; therapy development

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.

概括 尽管为寻找可卡因使用障碍的有效治疗方法付出了巨大的科学努力， 实现戒烟和防止旧病复发仍然是严峻的挑战。食欲素 (Orx) 系统 与动机、唤醒和压力的调节有关，使该系统成为 成瘾治疗的理想目标。可卡因会导致 Orx 系统发生适应不良的变化 反过来可能会维持可卡因的摄入并促进复发。我们的研究表明，敲击 下调下丘脑中的 Orx 基因会减弱长期可卡因的自我给药 在大鼠中，Orx 神经元在寻找可卡因期间被强烈招募。特别是奖励 寻找主要与下丘脑外侧 Orx 细胞的募集有关 （左）。 Orx 系统已被证明在介导多种药物的作用中发挥作用 通过投射到关键的大脑区域（例如前额皮质）来滥用药物，包括可卡因。 食欲素神经元密集投射到边缘下皮质（IL）。 IL主要受到牵连 反应抑制，已知可减弱依赖可卡因相关的行为 记忆，例如提示诱导的恢复。然而，关于该角色的证据存在相互矛盾的证据 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的作用，即 可卡因自我给药最近才开始进行研究。备受争议的数据 可卡因条件性恢复和可卡因自我给药的有限数据 妨碍了我们对 IL 参与抑制或促进的方式的理解 可卡因引发的行为（例如摄入和复发）。此外，精确的机制 使 IL 抑制或促进可卡因引发的行为仍然未知。考虑到 IL 在反应抑制中的功能和 LH Orx 在奖赏寻求中的功能，我们假设 LH Orx 输入到 IL 的活动将通过抑制来影响奖励驱动的行为 摄入可卡因和防止可卡因复发以及可卡因滥用的动机 参与并扰乱该电路。本项目将调查 LH Orx 的贡献 对可卡因成瘾周期的两个不同方面的 IL 进行预测：摄入和复发。 该项目将使用新的病毒载体，表达由以下人员独家激活的设计受体： 可以选择性地靶向大鼠 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，我们将测试是否 操纵（激活或抑制）LH Orx 对 IL 的输入会干扰可卡因的摄入和 提示诱导的恢复。该提案将提供有关特定项目的独特信息 LH[Orx]®IL 回路参与可卡因诱发行为的神经生物学。