Ferland Jacqueline-Marie N, Chisholm Alexandra, Abdalla Jasmina, Cinar Resat, Johnson Clare, Bradshaw Heather B, Hurd Yasmin L
Icahn School of Medicine at Mount Sinai, Departments of Neuroscience, Psychiatry; Addiction Institute of Mount Sinai, New York, NY, USA.
Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.
Mol Psychiatry. 2025 Jun;30(6):2718-2728. doi: 10.1038/s41380-024-02881-2. Epub 2025 Jan 15.
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 1 h 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.
焦虑症是全球精神负担的主要促成因素之一。近年来，大麻二酚（CBD）——一种大麻植物的无成瘾性成分——被认为具有潜在抗焦虑特性，且其数量急剧增加。这引发了多项临床试验，以检验CBD治疗焦虑症的潜力。然而，CBD的抗焦虑作用存在争议，一些研究报告称其对特质焦虑几乎没有影响，但对病理性焦虑有显著降低作用，这表明CBD的作用可能与触发或线索诱导行为有关。在此，我们研究了CBD对线索诱导和非线索诱导行为以及相关神经生物学基础的影响。为了研究CBD对线索诱导焦虑的影响，雄性大鼠接受恐惧条件反射实验（与电击相关的气味），随后评估回避行为。在焦虑评估前1小时给予CBD（10毫克/千克）。为了了解与行为相关的分子机制，我们研究了伏隔核壳（NAcSh）的转录组和脂质谱，该结构与线索介导的行为和厌恶有关。给予CBD显著降低了回避行为，但仅在反复暴露于电击配对线索的动物中出现。CBD对暴露于中性线索或线索行为反应编码的动物行为没有影响。RNA测序显示，电击配对线索对对照动物有重大影响，涉及从细胞骨架动力学到线粒体功能障碍等多种机制。电击配对线索还导致给予赋形剂动物的亚油酸升高，这与焦虑样行为相关。CBD要么逆转要么使这些线索诱导的分子表型正常化。CBD还激活了与突触可塑性信号传导和表观遗传机制相关转录本的脂质网络。这些结果表明，CBD可能特异性缓解显著的、条件性焦虑，并使NAcSh中相关生物学机制正常化，这可能为焦虑症的治疗干预提供指导。
