Alpha-casozepine (α CZP), a tryptic hydrolysate of milk casein is a decapeptide shown to promote sleep and produce anxiolytic or anticonvulsant activity. Intriguingly, studies indicate structural similarities to benzodiazepine (BZD)-like molecules (e.g., diazepam), resulting in positive modulation of γ-aminobutyric acid A type (GABA_A) receptors. However, some unexplained anomalous behaviour of α-CZP includes 1) 1000 times less affinity for BZD site on GABA_A receptor in vitro conditions, whereas in vivo it showed 10-fold increased affinity when compared to diazepam; 2) anxiolytic effects were observed only in stressed conditions and 3) unlike diazepam, it failed to exhibit dependence or habituation. Interestingly, neurosteroids like allopregnanolone or its analogues that are synthesized de novo have both genomic and non-genomic actions. The rapid nongenomic neuronal inhibition of these compounds is mediated by GABA_A receptors through autocrine and paracrine actions. Studies have shown that changes in the levels of neurosteroids during acute (rise) and chronic stress (decreased), consequently, altering the senetivity of GABA_A receptor subunits. Neurosteroids even at low concentration (nanomolar range) potentiate the response of GABA indirectly, while at higher concentrations they directly activate the receptor-channel complex. Interestingly, coadministration of neurosteroids and BZPs has shown not only to prevent the development of tolerance of BZP and augmented recovery from BZP withdrawal anxiety and hyperactivity in mice. The combination also produced synergetic anxiolytic effects. Taken together, the evidence suggests possible implications of neurosteroids in the actions of CZP via BZD receptors. The present hypothesis brings out the possible role of neurosteroids and the various factors that might participate in CZP-induce anxiolytic effects.

α-casozepine (α CZP) 是一种牛奶酪蛋白的胰蛋白酶水解物，是一种十肽，可促进睡眠并产生抗焦虑或抗惊厥活性。有趣的是，研究表明与苯二氮卓 (BZD) 样分子（例如地西泮）的结构相似，导致对 γ-氨基丁酸 A 型 (GABA _A ) 受体的正向调节。然而，α-CZP 的一些无法解释的异常行为包括 1)在体外条件下对 GABA _A受体上 BZD 位点的亲和力降低 1000 倍，而在体内与地西泮相比，它的亲和力增加了 10 倍；2) 仅在压力条件下观察到抗焦虑作用，3) 与地西泮不同，它没有表现出依赖性或习惯性。有趣的是，从头合成的别孕酮或其类似物等神经类固醇具有基因组和非基因组作用。这些化合物的快速非基因组神经元抑制是由 GABA _A受体通过自分泌和旁分泌作用介导的。研究表明，在急性（上升）和慢性压力（下降）期间神经类固醇水平的变化，从而改变了 GABA _A的敏感性受体亚基。即使在低浓度（纳摩尔范围）下，神经类固醇也会间接增强 GABA 的反应，而在较高浓度下，它们会直接激活受体-通道复合物。有趣的是，神经类固醇和 BZP 的共同给药不仅可以防止 BZP 耐受性的发展，还可以增强小鼠从 BZP 戒断焦虑和多动症中恢复的能力。该组合还产生协同抗焦虑作用。总之，证据表明神经类固醇可能通过 BZD 受体影响 CZP 的作用。目前的假设提出了神经类固醇的可能作用以及可能参与 CZP 诱导抗焦虑作用的各种因素。