Physiology and pharmacology of the GABA system: Focus on GABA receptors

Abstract

Wake and sleep states have long been known to be implemented by distinct synchronized neural oscillations. Changes in the pattern of neural oscillations have recently been recognized to be largely due to the impact of GABAergic regulation. Inhibitory interneurons are the main players in sculpting neuronal rhythms, controlling spike timing, selecting network assemblies and implementing brain states. A rich diversity of GABAergic interneurons imprints its activity, mediated through a comparably rich diversity of GABAA receptors. Pharmacologically, there is a clear division of labor among GABAA receptor subtypes. Sedation, a common denominator of GABAA receptor-related hypnotics, is mediated via α1GABAA receptors. However, the hypnotic EEG finger print of diazepam is largely linked to α2GABAA receptors, pointing to two distinct receptor systems for sleep regulation. Anxiety is a major impairment of sleep, which can be selectively controlled by α2 GABAA receptor modulators. Chronic pain, another frequent sleep impediment can be alleviated by α2/GABAA receptor modulators. Chronic pain, another frequent sleep impediment can be alleviated by α2/α3GABAA receptor modulators. Finally, cognitive deficits can be pharmacologically addressed by partial inverse agonists of α5GABAA receptors. Thus, in the future, it is conceivable that disease-specific hypnotics could be developed by combining the modulation of suitable GABAA receptor subtypes. GABAB receptors play a pharmacological role as target of γ-hydroxybutyrate, which is frequently used in the treatment of narcolepsy. Thus, as our understanding of GABAergic deficits in sleep disturbances increases, the strategic targeting of GABA receptor subtypes may represent a new approach for the personalized pharmacological management of sleep disorders.