School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Technion Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Mol Neurobiol. 2022 Aug;59(8):5070-5083. doi: 10.1007/s12035-022-02884-6. Epub 2022 Jun 6.
Δ-Tetrahydrocannabinol (Δ-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ-THC has similar affinities for CB/CB cannabinoid receptors. However, the effect of HU-308, a selective CB receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ-THC were studied with gene analysis. The effects of HU-308 on head twitch response (HTR), ear scratch response (ESR), and grooming behavior were compared between wildtype and CB receptor knockout (CB) mice, and in the presence/absence of DOI or SR141716A, a CB receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB mice. In juveniles, HU-308 inhibited HTR and ESR in the presence of DOI and SR141716A. HU-308 and beta-caryophyllene significantly increased HTR. In the left prefrontal cortex, DOI increased transcript expression of the CB receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/β-hydrolase domain-containing 6 (ABHD6) expression levels. CB receptors are required to reduce 5-HT-induced tics in adults. HU-308 has an off-target effect which increases 5-HT-induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB receptor agonists suggests that stimulation of the CB receptor may generate motor tics in children. Sex differences suggest that the CB receptor may contribute to the prevalence of TS in boys. The 5-HT-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids' levels in patients with TS.
Δ-四氢大麻酚（Δ-THC）可抑制抽动秽语综合征（TS）患者的抽搐。Δ-THC 对 CB/CB 大麻素受体具有相似的亲和力。然而，选择性 CB 受体激动剂 HU-308 对重复行为的影响尚未得到研究。使用基因分析研究了 2,5-二甲氧基-4-碘苯丙胺（DOI）诱导的运动样抽搐和 Δ-THC 的作用。比较了野生型和 CB 受体敲除（CB）小鼠以及存在/不存在 DOI 或 CB 受体拮抗剂/反向激动剂 SR141716A 时，HU-308 对摇头反应（HTR）、耳抓反应（ESR）和梳理行为的影响。在 CB 小鼠中，DOI 诱导的重复行为的频率高于野生型小鼠。HU-308 增加了成年 CB 小鼠中 DOI 诱导的 ESR 和梳理行为。在青少年中，HU-308 在 DOI 和 SR141716A 存在的情况下抑制 HTR 和 ESR。HU-308 和 β-石竹烯显著增加 HTR。在左前额叶皮质中，DOI 增加了 CB 受体和 GPR55 的转录表达，但降低了脂肪酸酰胺水解酶（FAAH）和 α/β-水解酶结构域包含 6（ABHD6）的表达水平。CB 受体是减少成年 5-HT 诱导抽搐所必需的。HU-308 具有脱靶效应，可增加成年雌性小鼠中 5-HT 诱导的运动样抽搐。选择性 CB 受体激动剂诱导的青少年 HTR 增加表明，CB 受体的刺激可能会在儿童中产生运动性抽搐。性别差异表明，CB 受体可能导致 TS 在男孩中的流行率增加。5-HT 诱导的内源性大麻素代谢酶表达水平降低可能解释了 TS 患者内源性大麻素水平升高的原因。
