Cannabidiol abrogates cue-induced anxiety associated with normalization of mitochondria-specific transcripts and linoleic acid in the nucleus accumbens shell

Anxiety disorders are one of the top contributors to psychiatric burden worldwide. Recent years have seen a dramatic rise in the potential anxiolytic properties ascribed to cannabidiol (CBD), a non-intoxicating constituent of the Cannabis Sativa plant. This has led to several clinical trials underway to examine the therapeutic potential of CBD for anxiety disorders. Yet, CBD’s anxiolytic effects are mixed with some studies reporting little to no impact on trait anxiety but significant reductions in pathological anxiety with suggestions that CBD’s effect may relate to triggered or cue-induced behavior. Here, we studied the effects of CBD on cued and non-cued behaviors and related neurobiological underpinnings. To investigate the effect of CBD on cue-induced anxiety, male rats underwent a fear conditioning protocol (odor associated with shock) followed by assessments of avoidance behavior. CBD (10 mg/kg) was administered 1hr prior to anxiety assessments. To understand molecular mechanisms associated with behavior, we investigated the transcriptome and lipid profile of the nucleus accumbens shell (NAcSh), a structure implicated in cue-mediated behaviors and aversion. Administration of CBD significantly reduced avoidance behavior, but only in animals repeatedly exposed to a shock-paired cue. CBD did not affect behavior in animals exposed to neutral cue or encoding of the cue behavioral response. RNA sequencing revealed substantial impact of the shock-paired cue in control animals, recruiting mechanisms ranging from cytoskeletal dynamics to mitochondria dysfunction. The shock-paired cue also resulted in elevated linoleic acid in vehicle animals which correlated with anxiety-like behavior. CBD either reversed or normalized these cue-induced molecular phenotypes. CBD also recruited lipid networks which correlated with transcripts involved in synaptic plasticity, signaling, and epigenetic mechanisms. These results suggest that CBD may specifically alleviate salient, conditioned anxiety and normalize related biological mechanisms in the NAcSh which may guide therapeutic interventions for anxiety disorders.焦虑障碍是全球精神疾病负担的首要诱因之一。近年来，大麻二酚（Cannabidiol, CBD）——大麻（Cannabis Sativa）植物的非精神活性成分——的潜在抗焦虑属性受到广泛关注，相关研究数量大幅增长，由此推动了多项旨在评估大麻二酚治疗焦虑障碍潜力的临床试验。然而，大麻二酚的抗焦虑效果并不一致：部分研究显示其对特质焦虑几乎无影响，却能显著降低病理性焦虑，且有研究提示其作用可能与触发式或线索诱导性行为相关。本研究探究了大麻二酚对线索诱导与非线索诱导行为的影响，及其相关的神经生物学基础。为探究大麻二酚对线索诱导性焦虑的作用，本研究以雄性大鼠为对象，先实施恐惧条件化范式（即气味与电击配对），随后对其回避行为进行评估，并于焦虑评估前1小时给予10 mg/kg的大麻二酚。为解析行为相关的分子机制，本研究对伏隔核壳区（nucleus accumbens shell, NAcSh）的转录组与脂质谱进行了分析，该脑区参与线索介导行为与厌恶反应的调控。结果显示，大麻二酚可显著降低大鼠的回避行为，但仅在反复暴露于电击配对线索的动物中观测到该效应；对于暴露于中性线索的大鼠，以及线索行为反应编码阶段的大鼠，大麻二酚未对其行为产生影响。RNA测序（RNA sequencing）结果表明，电击配对线索对对照组大鼠产生了显著影响，其激活的分子通路涵盖细胞骨架动态调控至线粒体功能障碍等多个层面。此外，电击配对线索还导致溶剂对照组大鼠的亚油酸（linoleic acid）水平升高，且该变化与焦虑样行为呈显著相关。大麻二酚可逆转或使这些线索诱导的分子表型恢复至正常水平，同时还调控了与突触可塑性、信号转导及表观遗传机制相关的脂质网络。本研究结果表明，大麻二酚可特异性缓解显著的条件化焦虑，并使伏隔核壳区中与之相关的生物学机制恢复正常，该发现可为焦虑障碍的治疗干预提供指导。