Gaboxadol - a new awakening in sleep
by
Wafford KA, Ebert B.
Merck, Sharp & Dohme,
Neuroscience Research Centre,
Terlings Park, Eastwick Road,
Harlow, Essex CM20 2QR, UK.
Curr Opin Pharmacol. 2005 Dec 16;

ABSTRACT

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 GABA(A) 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 GABA(A) 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.

Alcohol
GABA(B)
Sedatives
Gaboxadol
Benzo choices
Anticonvulsants
Benzodiazepines
Neuroactive steroids
Gaboxadol: structure
GABA(A) and fluoxetine
Anxiolytics and antidepressants
GABA, pain and the cerebral cortex
GABA(A) and genetically modified mice
Anxioselective compounds and GABA(A)
Alpha 1 and alpha 2 GABA(A) receptor subunits

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