Gaboxadol — a new awakening in sleep
Introduction
The major mechanism for neuronal inhibition in the adult mammalian central nervous system utilizes γ-aminobutyric acid (GABA)A receptors to reduce and control cell excitability. Playing such an important role has made GABAA receptors prime targets for therapeutic agents that cause sedation and hypnosis via enhancement of this inhibitory activity. Conversely, agents that block GABA-mediated inhibitory transmission, such as picrotoxin, cause increased cell firing and seizure activity. GABAA receptors are a heterogeneous family of ligand-gated ion channels selectively permeable to chloride, and can be sub-classified by their molecular composition. GABAA receptors are composed of five subunits, with current evidence supporting the combination of two α, two β and one additional subunit, either γ, δ or ɛ. The α, β and γ subunits can be subdivided into α1–6, β1–3 and γ1–3. The >20 receptor subtypes that have now been identified are thought to have distinct functions, as suggested by their unique pharmacological and biophysical properties and their cell- and region-specific distribution patterns [1, 2].
Section snippets
Benzodiazepines
Benzodiazepines are the most widely used group of hypnotics and mediate their effects through allosteric binding and potentiation of GABAA receptor-mediated chloride conductance. The majority of clinically used benzodiazepines bind with high affinity only to those receptors containing a γ2 subunit, the binding pocket of which is located between the α and γ subunit [3]. The majority of prescribed benzodiazepines behave as high-efficacy positive allosteric modulators with very little selectivity
Cell- and region-specific receptor targeting
In addition to regional specificity in the brain, GABAA receptors are also targeted to specific regions of the cell. Both the γ2 subunit and the receptor-associated protein gephyrin are required to associate and cluster GABAA receptors to postsynaptic membranes [11], although there is no evidence for a direct interaction between these proteins. Several other receptor subtypes, rather than being targeted to postsynaptic membranes, occupy either cell body or perisynaptic locations. Whether these
GABAA receptor agonists
Since the discovery of muscimol as a GABA receptor agonist and the subsequent realization that muscimol is selective for the ionotropic GABAA receptor subtype, several GABAA receptor agonists have been designed, synthesized and characterized in vitro. One of the most active and successful research groups in this area has been that of Krogsgaard-Larsen in Copenhagen, who have investigated the structural requirements for GABAA receptor activation. These studies have led to gradually refined
The thalamus and sleep pathways
The thalamus plays a crucial role in controlling the flow of information from sensory organs to the cortex, and acts as a gatekeeper in modifying and directing these signals appropriately. During sleep, sensory input is inhibited but thalamocortical activity continues, consolidating and processing information into memory [31]. During this time, oscillatory activity generated between the thalamus and cortex form the sleep rhythms that constitute slow wave sleep (SWS) and rapid eye movement (REM)
Selective activation of extrasynaptic receptors
Gaboxadol activates extrasynaptic receptors in relay neurons of the ventrobasal thalamus (VB) at relatively low concentrations (<1 μM) [23••, 24••], which correlates with the drug's sensitivity at α4βδ recombinant receptors and with the levels found in plasma at effective drug concentrations [35]. Gaboxadol has no effect on synaptic currents at concentrations of up to 3 μM. The tonic current in the VB is markedly reduced in the β2 subunit knockout mouse, suggesting that α4β2δ underlies this tonic
Interactions with benzodiazepines and alcohol
It is well established that coadministration of benzodiazepines and alcohol produces a synergistic pharmacological response, usually measured as increased sedation or ataxia [46]. No such synergism is observed in vivo or in brain slice preparations when combining gaboxadol with either benzodiazepines or alcohol, supporting the notion that gaboxadol exerts its effects at a different population of receptors [47, 48]. Furthermore, when rats are rendered insensitive to the modest motor coordination
Gaboxadol effects on sleep
Lancel and coworkers demonstrated in 1997 that gaboxadol has sleep-promoting effects as demonstrated by significant reductions in sleep onset latency and increases in sleep duration. In addition, gaboxadol exerts unique effects on sleep architecture in both rats and humans, inducing a significant increase in SWS and slow wave activity (SWA; a mathematical analysis of the low frequency EEG waveforms that predominate during SWS) without suppressing REM sleep [56, 57]. Similar effects in rats were
Significance of slow wave sleep
Sleep is a bimodal state comprising two neurochemically and electrophysiologically distinct substates — REM and NREM sleep — which alternate to form a 90–110 min cycle. NREM sleep stages 1 (superficial sleep) to 4 (deep sleep) vary in depth, as defined by an arousal threshold. NREM stages 3 and 4 together define SWS, the levels of which have been shown to be under tight homeostatic control. More precisely, following sleep deprivation or (chronic) sleep restriction, levels of SWS and SWA
Conclusions
Current data from in vitro and in vivo studies demonstrate that gaboxadol achieves its hypnotic effects via a fundamentally different mechanism from that of the benzodiazepine receptor agonists. Functional selectivity for the tonic current generated by extrasynaptic GABAA receptors containing the δ-subunit, with little effect on synaptic currents mediated by benzodiazepine receptor agonist-sensitive receptors, uniquely characterizes gaboxadol. Significant differences in sleep architecture and
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank John Lapolla for his helpful discussion and suggestions during preparation of the manuscript.
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