Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide’s classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of Crbn (Crbn YW/AA knock-in mice). Thalidomide increased non-REM sleep time in Crbn YW/AA knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and Crbn YW/AA homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide’s hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABA_A-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.

沙利度胺通过与大脑（CRBN）结合而发挥其致畸作用和免疫调节作用，从而抑制/修饰由Cullin4-DDB1-ROC1 E3连接酶复合物组成的CRBN介导的泛素化途径。然而，沙利度胺经典催眠作用的机制仍未得到充分探索。在这里，我们通过产生带有Crbn抗沙利度胺抗性突变体等位基因的小鼠（Crbn YW / AA敲入小鼠）来检查CRBN是否参与沙利度胺的催眠作用。沙利度胺增加了Crbn YW / AA敲入纯合子和杂合子的非REM睡眠时间，其程度与野生型同窝仔动物相似。沙利度胺同样抑制了从野生型和野生型获得的皮层中的兴奋性突触传递。Crbn YW / AA纯合敲入小鼠，不影响GABA能抑制。沙利度胺诱导视光上含维加压素的神经元中Fos表达，并降低结核母乳核中Fos表达。因此，沙利度胺的催眠作用似乎与全身麻醉药和GABA _A活化镇静剂共享某些下游机制，但不涉及致畸性CRBN介导的泛素/蛋白酶体途径。