Certain metabolites of progesterone and deoxycorticosterone are established as potent and selective positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. Upon administration these steroids exhibit clear behavioural effects that include anxiolysis, sedation and analgesia, they are anticonvulsant and at high doses induce a state of general anaesthesia, a profile consistent with an action to enhance neuronal inhibition. Physiologically, peripherally synthesised pregnane steroids derived from endocrine glands such as the adrenals and ovaries function as hormones by crossing the blood brain barrier to influence neuronal signalling. However, the demonstration that certain neurons and glial cells within the central nervous system (CNS) can synthesize these steroids either de novo, or from peripherally derived progesterone, has led to the proposal that these steroids (neurosteroids) can additionally function in a paracrine manner, to locally influence GABAergic transmission. Steroid levels are known to change dynamically, for example in stress and during pregnancy. Given that GABA(A) receptors are ubiquitously expressed throughout the central nervous system, such changes in steroid levels would be predicted to cause a global enhancement of inhibitory neurotransmission throughout the brain, a scenario that would seem incompatible with a physiological role as a selective neuromodulator. Here, we will review emerging evidence that the GABA-modulatory actions of the pregnane steroids are highly selective, with their actions being brain region and indeed neuron dependent. Furthermore, the sensitivity of GABA(A) receptors is not static but can dynamically change. The molecular mechanisms underpinning this neuronal specificity will be discussed with particular emphasis being given to the role of GABA(A) receptor isoforms, protein phosphorylation and local steroid metabolism and synthesis.

中文翻译：

---

GABAA受体的神经甾体调节。

孕酮和脱氧皮质酮的某些代谢产物被确定为A型γ-氨基丁酸（GABA（A））受体的强效和选择性正变构调节剂。给药后，这些类固醇表现出明显的行为作用，包括抗焦虑，镇静和镇痛作用，它们具有抗惊厥作用，并且在高剂量时会引起全身麻醉，这与增强神经元抑制作用相一致。在生理上，源自内分泌腺（如肾上腺和卵巢）的外周合成孕激素类固醇通过穿越血脑屏障影响神经元信号传导而起着激素的作用。但是，证明中枢神经系统（CNS）中的某些神经元和神经胶质细胞可以从头合成这些类固醇，或来自周围来源的孕激素，导致提出这样的建议，即这些类固醇（神经类固醇）还可以旁分泌的方式起作用，以局部影响GABA能传递。已知类固醇水平会动态变化，例如在压力下和怀孕期间。假设GABA（A）受体在整个中枢神经系统中普遍表达，那么类固醇水平的这种变化预计会导致整个大脑中抑制性神经传递的整体增强，这种情况似乎与作为选择性神经调节剂的生理作用不兼容。在这里，我们将回顾新兴证据，表明孕激素类固醇的GABA调节作用具有高度选择性，其作用是大脑区域，实际上是神经元依赖性的。此外，GABA（A）受体的敏感性不是一成不变的，而是可以动态变化的。将讨论支持这种神经元特异性的分子机制，并特别强调GABA（A）受体同工型，蛋白质磷酸化以及局部类固醇代谢和合成的作用。