Wafford Keith A, Ebert Bjarke
Merck, Sharp & Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
Curr Opin Pharmacol. 2006 Feb;6(1):30-6. doi: 10.1016/j.coph.2005.10.004. Epub 2005 Dec 20.
Drugs that enhance synaptic gamma-aminobutyric acid (GABA)ergic neurotransmission are widely utilized in the clinical setting. Barbiturates and benzodiazepine receptor agonists, for example, both potentiate an inhibitory chloride conductance through GABA-gated channels, and thereby achieve their sedative-hypnotic effects. The primary locus of action of these agents, and indeed most neuroactive drugs, is the postsynaptic junction. By contrast, gaboxadol, a selective extrasynaptic GABA receptor agonist and late-stage investigational treatment for insomnia, acts on a unique delta-containing GABAA receptor subtype found exclusively outside of the synapse. Although the mechanistic details of extrasynaptic neurotransmission remain to be fully established, it is now clear that these receptors demonstrate unique pharmacological, biophysical and electrophysiological properties. Importantly, the delta-containing GABAA receptor subtype activated by gaboxadol is highly expressed in the thalamus, where it might behave as a 'gain control' (independently controlling the strength of signals) in the corticothalamic pathways that govern sleep-relevant neuronal oscillations. This unique mechanism has contributed to our increased understanding of sleep mechanisms, and targeting of this system offers potential advantages over existing insomnia treatments.
增强突触γ-氨基丁酸（GABA）能神经传递的药物在临床中广泛应用。例如，巴比妥类药物和苯二氮䓬受体激动剂均通过GABA门控通道增强抑制性氯离子电导，从而产生镇静催眠作用。这些药物以及实际上大多数神经活性药物的主要作用位点是突触后连接。相比之下，加波沙朵是一种选择性突触外GABA受体激动剂，也是用于失眠治疗的后期研究药物，它作用于一种独特的含δ亚基的GABAA受体亚型，这种亚型仅在突触外发现。尽管突触外神经传递的机制细节仍有待完全明确，但现在很清楚的是，这些受体具有独特的药理学、生物物理学和电生理学特性。重要的是，加波沙朵激活的含δ亚基的GABAA受体亚型在丘脑中高度表达，在那里它可能在控制与睡眠相关神经元振荡的皮质丘脑通路中充当“增益控制”（独立控制信号强度）。这种独特机制有助于我们加深对睡眠机制的理解，并且针对该系统的治疗相对于现有的失眠治疗方法具有潜在优势。
