The GABAergic System: An Overview of Physiology, Physiopathology and Therapeutics

Abstract

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, where it is widely distributed. GABA has an important role in neurodevelopment, and depending on the period of development, its action can be excitatory or inhibitory. In prenatal stages, GABA is excitatory, and in the adult stage, GABA acquires an inhibitory function in the nervous system and modulates the function of other organs and systems including the endocrine system and the immune system. Disorders in the function of GABA are responsible for various pathologies, both neurological and non-neurological, and include epilepsy, anxiety, depression, schizophrenia, endocrine disorders and immunological disorders. In the present narrative review, we show that the activity of GABA depends on the synthesis, degradation, membrane transport and the presence of specific GABA receptors, present in both nervous tissue and non-neural tissue. We describe general aspects of the physiology, physiopathology, and pharmacotherapeutics of the GABA system, and finally, we emphasize that although there are multiple GABAergic therapeutic options, more research is required into the GABA system since future applications may be broad.

Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep

“…Three different GABA receptors, GABA A , GABA B , and GABA C , are involved in the regulation of sleep and arousal (albeit to different extents) [2,25]. The most commonly used hypnotics exert their effect on GABA systems, most notably through allosteric modulation of the benzodiazepine site [26][27][28]. Similarly, many herbal medicines have been proposed to enhance GABAergic signaling, many through interactions with the GABA A receptor [13].…”

“…Barbiturates do not show selective affinity to different receptor compositions of GABA A . Second-generation sleep aids (benzodiazepines) are GABA A allosteric modulators that bind to the interface between the α and the γ subunits across a range of receptor compositions [27,29,31]. Recently developed third-generation non-benzodiazepine hypnotics include, among others, zopiclone (a cyclopyrrolone), zolpidem (an imidazopyridine), and zaleplon (a pyrazolopyrimidine), which are sometimes collectively called the "Z drugs" [32].…”

“…GABA B receptors are slow-acting metabotropic G-protein-linked dimers containing one GABA B1 (GABA B1a or GABA B1B ) and one GABA B2 subunit [25,28,29] (Figure 2). Fewer drugs have been developed to target the GABA B receptor, baclofen being the most popular agonist, and there are less clinical data available than for the GABA A receptor [27,35]. Although GABA B agonists may promote sleep by increasing the duration of NREM and REM sleep, the effect is believed to be largely off-target [28,36].…”

“…The subclass of GABA A receptors containing ρ subunits is often called GABA C or GABA-ρ; they belong to the same family of fast-acting pentameric, ligand-gated Clion channels as GABA A [25,27,41] (Figure 3). Although both GABA A and GABA C receptors bind GABA, they have separate sets of agonists and antagonists.…”

GABAA receptor mapping in human using non-invasive electrophysiology

“…The link between GABA and macroscopic oscillations observed in MEG is likely mediated by the functional inhibitory role of GABA receptors, which are broadly categorised as fast, ionotropic GABA A and slower G-protein coupled GABA B , although there exist subtypes of each (Belelli et al, 2009;Vargas, 2018;Whiting, 2003). The currents mediated by both of these receptor types have been implicated in oscillation generation through control of recurrent excitation-inhibition (Atallah & Scanziani, 2009;Brunel & Wang, 2003;Galarreta & Hestrin, 1998;Kohl & Paulsen, 2010;Krupa et al, 2014), whereby the GABAergically-mediated inhibitory currents exert temporal control over the firing and activity of excitatory principal cells (Bartos et al, 2007;Whittington et al, 2000).…”