PDF(Pubmed)
Abstract：
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.
摘要：
大麻素受体1（CB1）是著名的Δ9-四氢大麻酚（THC）的靶标，这是大麻的活性成分。CB1的抑制经常被建议作为许多疾病的药物靶标或基因治疗(例如，肥胖，帕金森病)。然而,受CB1影响的大脑网络仍然难以捉摸，在一项临床试验中，意想不到的心理影响产生了可怕的后果。为了更好地了解CB1抑制的全脑效应，我们在CB1基因完全敲除（cnr1-/-）以及CB1反向激动剂利莫那班的情况下对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脑功能（网络活动和方向均匀性）。在cnr1-/-小鼠中，白质（两性）和功能方向均匀性（雄性小鼠）在整个大脑中发生了改变，但网络活动基本上没有改变。相反，在利莫那班,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，主要在已知被THC改变的网络中(例如，大脑皮层,海马结构）。然而,利莫那班并没有改变我们在cnr1-/-结果和以前的cnr1-/-小鼠行为研究中发现的许多大脑区域(例如，丘脑,外边缘区域)。这表明CNR1的慢性丢失与短期抑制有很大不同，巧妙地重新连接大脑，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CB1中的病理突变(例如，慢性疼痛)并不总是提供对CB1抑制副作用的洞察力(例如，临床抑郁症)，因此，敦促对任何抑制CB1的药物进行更多的临床前研究。
