The cannabinoid receptor 1 (CB₁) is famous as the target of Δ⁹-tetrahydrocannabinol (THC), which is the active ingredient of marijuana. Suppression of CB₁ is frequently suggested as a drug target or gene therapy for many conditions (e.g., obesity, Parkinson’s disease). However, brain networks affected by CB₁ remain elusive, and unanticipated psychological effects in a clinical trial had dire consequences. To better understand the whole brain effects of CB₁ suppression we performed in vivo imaging on mice under complete knockout of the gene for CB₁ (cnr1^–/–) and also under the CB₁ inverse agonist rimonabant. We examined white matter structural changes and brain function (network activity and directional uniformity) in cnr1^–/– mice. In cnr1^–/– mice, white matter (in both sexes) and functional directional uniformity (in male mice) were altered across the brain but network activity was largely unaltered. Conversely, under rimonabant, functional directional uniformity was not altered but network activity was altered in cortical regions, primarily in networks known to be altered by THC (e.g., neocortex, hippocampal formation). However, rimonabant did not alter many brain regions found in both our cnr1^–/– results and previous behavioral studies of cnr1^–/– mice (e.g., thalamus, infralimbic area). This suggests that chronic loss of cnr1 is substantially different from short-term suppression, subtly rewiring the brain but largely maintaining the network activity. Our results help explain why pathological mutations in CB₁ (e.g., chronic pain) do not always provide insight into the side effects of CB₁ suppression (e.g., clinical depression), and thus urge more preclinical studies for any drugs that suppress CB₁.

中文翻译：

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反向激动剂下的静息态大脑网络与大麻素受体 1 完全敲除的比较

大麻素受体 1 (CB ₁ ) 作为大麻活性成分Δ ⁹ -四氢大麻酚 (THC)的靶标而闻名。 CB ₁的抑制经常被建议作为许多疾病（例如肥胖、帕金森病）的药物靶标或基因治疗。然而，受 CB ₁影响的大脑网络仍然难以捉摸，临床试验中意想不到的心理影响产生了可怕的后果。为了更好地了解 CB ₁抑制对全脑的影响，我们对 CB ₁基因完全敲除( cnr1 ^–/– ) 以及 CB ₁反向激动剂利莫那班的小鼠进行了体内成像。我们检查了cnr1 ^–/–小鼠的白质结构变化和大脑功能（网络活动和方向均匀性）。在cnr1 ^–/–小鼠中，大脑中的白质（两性）和功能方向均匀性（雄性小鼠）发生了改变，但网络活动基本上没有改变。相反，在利莫那班作用下，功能方向均匀性没有改变，但皮质区域的网络活动发生了改变，主要是已知被 THC 改变的网络（例如，新皮质、海马结构）。然而，利莫那班并没有改变我们的cnr1 ^–/–结果和之前cnr1 ^–/–小鼠行为研究中发现的许多大脑区域（例如丘脑、边缘下区）。这表明cnr1的慢性丢失与短期抑制有很大不同，它巧妙地重新连接了大脑，但在很大程度上维持了网络活动。我们的结果有助于解释为什么CB ₁的病理突变（例如慢性疼痛）并不总能深入了解CB ₁抑制的副作用（例如临床抑郁症），因此敦促对任何抑制CB _{1 的}药物进行更多的临床前研究。