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Hinton Tina, and Johnston Graham A.R. (2018) GABA, The Major Inhibitory Neurotransmitter in
the Brain. Reference Module in Biomedical Sciences. Elsevier. 5-Oct-18 doi: 10.1016/B978-0-12-
801238-3.96594-2.
Introduction 1
GABA Conformations 1
GABA Synthesis 1
GABA Release 2
GABA Receptors 3
GABAA Receptors 3
GABAA receptors and tonic inhibition 3
GABAA receptor antagonists 4
GABAA receptor agonists 5
Modulation of GABAA receptors 5
Benzodiazepine and related agents 5
Flavonoids 7
Steroids and stress 8
Ethanol 10
GABAB Receptors 10
GABAC Receptors (Also Known as GABAA-r or GABA-r Receptors) 11
GABA Transport 11
GABA Metabolism 12
GABA Beyond the Central Nervous System 12
Conclusion 13
Acknowledgment 13
References 13
Introduction
Simple molecule, complex function: GABA (derived from the old name g-aminobutyric acid for 4-aminobutanoic acid) is a
neurotransmitter of major significance in the brain, being released by up to 40% of neurons to activate chloride channels resulting
generally in inhibition of firing (Bowery and Smart, 2006). GABA was first identified in the brain in 1950 following its earlier
discovery in microbes and plants (Fig. 1).
GABA has multiple roles in the brain. GABA is present in large amounts in the brain, distributed in distinctly different cellular
pools reflecting its multiple functions (Waagepetersen et al., 1999). Its ubiquitous presence in the brain and spinal cord means that
almost all neurons either release GABA, express GABA receptors, or are innervated by neurons that do. Thus, most brain functions
are likely to involve GABA as a neurotransmitter. In addition to its role as a neurotransmitter of major significance, it functions as an
important metabolite and a neurotrophic agent.
GABA mechanisms are thought to be involved in anesthesia, anxiety, epilepsy, memory, neurodegenerative disorders, schizo-
phrenia, sleep, stress, cardiovascular and neuroendocrine function. Many agents act through GABA mechanisms including barbi-
turates, benzodiazepines, ethanol, flavonoids, general anesthetics, and neuroactive steroids (Froestl, 2011).
GABA Conformations
GABA interacts with a variety of binding sites on enzymes, receptors, and transporters. The conformational flexibility of GABA is
considered to be important for these interactions. Conformationally restricted analogs of GABA are able to selectively interact with
different GABA binding sites. Their activity indicates that different conformations of GABA interact with the different binding sites,
with the conformationally flexible GABA key able to uniquely interact with the different locks.
The conformational flexibility of GABA may be restricted by incorporation of unsaturated carbon–carbon bonds in the GABA
backbone, as in cis- and trans-4-aminocrotonic acid, or binding the backbone carbon–carbon bonds with a ring structure, as in
CAMP, or both as in muscimol and THIP (Fig. 2). Conformational restriction may also be achieved by addition of a heavy group
such as in baclofen. These agents each have selective actions on aspects of the GABA system (Johnston, 2014, 2016).
Fig. 1 GABA, zwitterionic structure and different low energy conformations (shapes).
Fig. 2 Conformationally restricted analogs of GABA and their selective actions on aspects of the GABA system.
GABA Synthesis
GABA is synthesized from L-glutamate via a-decarboxylation by glutamate decarboxylase (GAD). As the rate-limiting enzyme for
GABA synthesis, inhibition of GAD results in a decrease in GABA levels in the brain resulting in an increase in neuronal excitation
and ultimately convulsions.
Glutamine in astrocytes is a major source of GABA via glutamate, as inhibition of glutamine transport reduces GABA levels.
Other sources of GABA may include homocarnosine, ornithine, and putrescine.
GAD exists in two isoforms with different molecular weights, subcellular distributions, and regulatory properties encoded by
different genes on different chromosomes (Waagepetersen et al., 1999). GAD65 is associated primarily with vesicles in GABA-
containing nerve terminals, therefore it is thought to be involved in the synthesis of GABA mediating fast synaptic inhibition. GAD67
is more widely distributed in cytoplasm, found in neuron terminals and predominantly cell bodies, and is involved in the metabolic
function of GABA via the tricarboxylic acid cycle (Waagepetersen et al., 1999).
Anti-GAD antibodies are associated with autoimmune neurological disorders as well as type 1 diabetes as a result of GABA being
expressed in b-cells of the pancreas (Mitoma et al., 2017). Disorders of GAD are found in schizophrenia and bipolar disorder.
GABA Release
The vesicular release of GABA from presynaptic terminals following depolarization is calcium-dependent and is blocked by tetanus
toxin, a convulsant that also blocks the release of glycine, an important inhibitory transmitter in the spinal cord. GABA is also
released from other than presynaptic terminals, for example, from astrocytes by reverse action of GABA transporters or by other
nonvesicular release mechanisms (Koch and Magnusson, 2009). GABA may act as a “gliotransmitter” released from glial cells to
activate GABA receptors on neighboring neurons (Yoon and Lee, 2014).
GABA Receptors
Synaptic receptors for GABA may be divided into two classes based on their mechanism of action. Ionotropic GABA receptors act as
ligand-gated chloride channels. Metabotropic GABA receptors act as G protein-coupled receptors. These two classes were originally
termed GABAA and GABAB receptors on the basis of sensitivity to the convulsant alkaloid, bicuculline, and the central nervous
system depressant and skeletal muscle relaxant, baclofen. GABAA receptors are antagonized by bicuculline and insensitive to
baclofen while GABAB receptors are insensitive to bicuculline and sensitive to baclofen. This division has however been confounded
by the finding of ionotropic receptors that are insensitive to both bicuculline and baclofen. These receptors have been widely called
GABAC receptors, based on their distinctive structure, pharmacology, and physiology.
GABAA Receptors
These receptors belong to the superfamily of CYS-loop receptors that include ionotropic receptors for acetylcholine (nicotinic
receptors), glycine and 5-hydroxytryptamine (5HT3 receptors). GABAA receptors are heteromeric complexes made up of five protein
subunits, usually of three different types of subunits. In general, each subunit has a large extracellular N-terminal domain containing
the GABA binding site, a short extracellular C-terminal and four transmembrane domains with the second transmembrane forming
the walls of a chloride channel in combination with the other protein subunits. Activation of the chloride channel in mature
neurons results in the influx of chloride ions which stabilizes the membrane potential, thereby reducing excitatory depolarization of
the postsynaptic membrane. Intracellular chloride concentrations are regulated by the sodium–potassium–chloride cotransporter
NKCC1 and potassium-chloride cotransporter 2 (KCC2). Developmental changes in the cotransporters can mean that GABA has a
predominately depolarizing action in immature neurons changing to a hyperpolarizing action at maturity. The shift in action can be
influenced by a variety of factors including neonatal maternal separation (Furukawa et al., 2017), amyloid precursor protein
(Doshina et al., 2017), and immune activation (Skilbeck et al., 2018).
A total of 16 GABAA subunits have been identified in humans: six a-subunits, three b-subunits, three g-subunits, and d-, e-, y-,
and p-subunits. In addition there are splice variants and point mutations. Three r-subunits have been described that are sometimes
classified as GABAA receptor subunits on the basis of sequence similarity but these are more frequently classified as GABAC receptor
subunits. Different combinations of subunits result in different properties of GABAA receptors (Möhler, 2015). Thus there are a
myriad of subunit combinations making up a huge variety of possible GABAA receptors, making them the most complex of
neurotransmitter receptors. The most abundant pentameric isoform contains two a1-, two b2-, and one g2-subunits. Studies using
concatenated subunits indicate that the subunits are arranged g2–b2–a1–b2–a1 counterclockwise forming the ion channel as
viewed from the cell exterior (Sigel and Steinmann, 2012). Recombinant receptor combinations expressed in vectors such as Xenopus
oocytes together with in vivo gene knock out and knock in studies show that generalizations may be made concerning particular
combinations. Thus, activation of a1bg2 GABAA receptors mediates sedation, amnesia and anticonvulsant effects, whereas a2bg2
receptors mediate anxiolytic and myorelaxant effects and a5bg2 receptors influence learning and memory.
The mix of GABAA receptor subunits can be altered as in the so-called alpha subunit switch whereby a1- and a2-subunits exhibit
age-dependent expression. In general, a1-subunits predominate in adult brain and a2-subunits are more abundant in younger
tissue (Davis et al., 2000). Early-life environment has long-lasting effects on the mix of GABAA receptor subunits influencing adult
behavior (Skilbeck et al., 2018).
Subtype selective agents are being intensively sought in order to overcome the relative lack of selectivity of many therapeutic
agents acting on GABAA receptors. For example, unlike benzodiazepines, an anxiolytic agent devoid of addictive, amnesia and
sedative effects would be highly desirable (Skolnick, 2012). A very successful new therapeutic agent is S44819, a highly selective
competitive antagonist of GABAA receptors that contain the a5-subunit (Etherington et al., 2017). It is an orally active cognitive
enhancer acting at the orthosteric site at the a–b interface on extrasynaptic GABAA receptors to reduce tonic inhibition. Other agents
are known to act as negative allosteric modulators by binding to the benzodiazepine recognition site between at the a5–g2 subunits.
Agents that are selective for a5 subunit-containing GABAA receptors enhance cognitive performance in a variety of animal models
without sedative or proconvulsive effects.
Fig. 3 Antagonists that distinguish between the three major classes of GABA receptors.
specificity for GABAA receptors. Subject to these considerations, bicuculline and its quaternary salts continue to be used extensively
as GABAA receptor antagonists in experimentation.
Gabazine (Fig. 3, also known as SR 95531) is a relatively specific, potent and competitive antagonist of GABAA receptors
(Heaulme et al., 1986). Structural analogs of gabazine have been developed as more potent agents (Iqbal et al., 2011). Gabazine
analogs incorporating photoactive groups, such as GZ-B1, have been developed as photo-activated antagonists of GABAA receptors
(Mortensen et al., 2014). These antagonists provide dynamic tools for visualizing GABAA receptors, permitting a novel means of
investigating receptor location, function, and trafficking (Mortensen et al., 2014).
S44819 (Fig. 3, Egis-13,529), is a novel oxazolo-2,3-benzodiazepine derivative that selectively inhibits GABAA receptors that
contain the a5-subunit (Etherington et al., 2017). It appears to act as a competitive antagonist at the orthosteric site at the a–b
subunit interface of GABAA receptors containing only a5 subunits and enhances cognitive performance in a variety of animal
models without sedative or proconvulsive effects. S44819 has been shown in healthy young humans to be orally active, reaching the
cerebral cortex on oral administration where it increases cortical excitability, acting on extrasynaptic receptors to reduce tonic
inhibition (Darmani et al., 2016). S44819 and related a5 selective agents show promise as therapeutic agents.
Other important classes of antagonists include agents derived from 4-PIOL (Krall et al., 2015). Of particular interest is DPP-4-
PIOL that selectively antagonizes tonic over phasic GABAergic currents in the hippocampus, suggesting a degree of subunit
specificity (Boddum et al., 2014). Salicylidene salicylhydrazide has been reported as a potent antagonist of GABAA receptors
containing the b1 subunit using a high throughput screen (Thompson et al., 2004). The most potent GABAA receptor antagonist is
the convulsant steroid derivative RU5135, being some 500 times more potent than bicuculline (Hunt and Clementsjewery, 1981). It
acts as a competitive antagonist, sharing a common site of action with bicuculline. However, it lacks specificity, as it is also a glycine
receptor antagonist sharing a common site of action with strychnine (Simmonds and Turner, 1985). Terpenoids isolated from Salvia
triloba including ursolic acid, carnosol, oleanolic acid, and rosmanol act as nonconvulsant GABAA receptor antagonists (Abselhalim
et al., 2014).
range of structurally diverse chemicals was found to interact with benzodiazepine modulatory sites on GABAA receptors, leaving
GABAB and GABAC receptors largely unaffected.
Benzodiazepines have no direct action on GABAA receptors. Instead, they enhance the action of GABA by increasing the
frequency of ion channel openings. In contrast, barbiturates and ethanol increase the duration of channel openings and thus
increase the maximal effect of GABA. Barbiturates also have an allosteric agonist action on GABAA receptors, in other words they can
directly activate the receptor at high concentrations. As a result they are much more dangerous drugs than benzodiazepines, thus
benzodiazepines have replaced barbiturates as therapeutic agents. Agents such as DMCM have the opposite effect, decreasing the
action of GABA. This incorrectly led to the concept of “inverse agonist.” DMCM is correctly described as a negative allosteric
modular. True inverse agonists act at constitutively active G protein-coupled receptors (Fig. 4).
Benzodiazepines bind at the interface of the a- and g-subunits. The a-subunit requires a histidine residue as in a1-, a2-, a3-, and
a5-subunits. GABAA receptors containing a1-subunits are associated with stronger hypnotic and sedative effects of benzodiazepines,
while those containing a2- and a3-subunit are stronger anxiolytics (Crestani and Rudolph, 2015; Fritschy, 2015). Receptors
containing a5-subunits are associated with memory (Etherington et al., 2017). The therapeutic potential for agents acting selectively
on GABAA receptor subtypes is considerable to areas such as affective disorders, autism, Down syndrome, and schizophrenia
(Rudolph and Möhler, 2014).
Caution should be used in interpreting the many studies using flumazenil as a probe for GABAA receptor activity as not all
GABAA receptors are sensitive to this silent allosteric modulator. Such studies generally only pick up GABAA receptors containing g2-
subunits. Benzodiazepines have been shown to act on GABAA receptors by “two distinct and separable mechanisms” (Walters et al.,
2000). At low concentrations (nanomolar) they modulate in a manner sensitive to flumazenil, whereas at higher concentrations
(micromolar) they act in a flumazenil-insensitive manner. The high affinity action is confined to GABAA receptors containing the
g2-subunit. In adult brain, g2-subunits are much more abundant that g1 or g3. When g1 replaces g2, flumazenil changes from a
silent allosteric modulator to a positive allosteric modulator. Transgenic g2 knockout mice are insensitive to low doses of
benzodiazepines. The significance of the flumazenil-insensitive, low affinity site of benzodiazepine action remains somewhat
enigmatic (Walters et al., 2000). It may be related to the flumazenil-insensitive actions of many flavonoids (Hinton et al., 2017), as
will be discussed below.
Initially described as a peripheral benzodiazepine receptor, translocator protein (TSPO) binds a variety of benzodiazepine-like
drugs and is involved in cholesterol transport across the outer mitochondrial membrane in many tissues. It is a target for anxiety and
neurological disorders (Nothdurfter et al., 2012).
So-called nonbenzodiazepines that bear no obvious chemical resemblance to benzodiazepines have been developed for
insomnia, including drugs such as zolpidem. These “Z-drugs” act as positive allosteric modulators of a1-containing GABAA
receptors, binding to the benzodiazepine binding site. Their relative selectivity offers some advantages over benzodiazepines, but
they are not without their problems (Gao and Smith, 2010).
The term endozepine is used to describe endogenous compounds with effects similar to benzodiazepines (Farzampour et al.,
2015). They include the protein DBI (diazepam binding inhibitor) and oleamides. Endogenous cannabinoids also positively
modulate GABAA receptors (Sigel et al., 2011; Bakas et al., 2017).
Flavonoids
In the 1990s, scientists in Argentina described flavonoids as “a new family of benzodiazepine receptor ligands” (Medina et al.,
1997). They have proved to be much more than that, far surpassing the benzodiazepines in their range of actions of GABAA
receptors (Hanrahan et al., 2015). Flavonoids are consumed extensively in our diet. Many are able to cross the blood brain barrier
into the brain and constitute agents capable of influencing the function of GABAA receptors. In addition to the large range of
flavonoids that occur naturally, there are a considerable number of synthetic flavonoids that influence GABAA receptors. Natural
and synthetic flavonoids are known to act as positive, silent and negative allosteric modulators as well as allosteric agonists (Hinton
et al., 2017). Many of these actions are insensitive to flumazenil.
The flavones hispidulin, luteolin, and apigenin (Fig. 5) are closely related structurally but show differing profiles of activity at
GABAA receptors and differing effects in vivo, demonstrating that small differences in chemical structure have profound effects on
the biological properties of these agents.
Hispidulin is an anticonvulsant from sage (Salvia officinalis) that acts as a positive allosteric modulator on recombinant a1b2g2
GABAA receptors that is only partially blocked by flumazenil (Kavvadias et al., 2004). Like many flavonoids, it exhibits a biphasic
action and is approximately equipotent at each of six different a-subunit containing GABAA receptors—a1,2,3,5,6b2g2S, enhancing
at low concentrations (EC50 0.8–5 mM) and inhibiting at higher concentrations (>30 mM).
Luteolin, found in many plants including green peppers and celery, has an anxiolytic and sedative action on experimental
animals that is insensitive to flumazenil, consistent with acting as a positive allosteric modulator at GABAA receptors (Hinton et al.,
2017). Although structurally related to hispidulin, it does not act as an anticonvulsant. Its association with GABAA receptors is
suggested by the ability to promote GABA-mediated chloride influx in human neuroblastoma cells, which is attenuated by the
GABAA receptor antagonist bicuculline.
Apigenin, an anxiolytic found in chamomile, has complex modulatory actions on GABAA receptors. Most interesting is the
ability of apigenin to modulate the first order modulation of GABAA receptors by benzodiazepines such as diazepam (Campbell
et al., 2004). This second order modulation is selective for diazepam first order modulation—it has not been observed for
pentobarbitone or allopregnanolone modulation. Second order modulation has been noted in other systems (Mesce, 2002; Ribeiro
and Sebastiao, 2010) and may represent an obscure novel mechanism of drug action deserving further investigation, with the
potential to lead to decreased therapeutic doses.
()-Epigallocatechin gallate (EGCG, Fig. 5), the major flavonoid in green tea (Camellia sinensis), is an order of magnitude more
potent than apigenin as a second order modulator (Campbell et al., 2004). In addition, it was been found to reverse b-carboline
negative allosteric modulation of GABA action (Vignes et al., 2006). This indicates that EGCG may act as a second-order modulator
with respect to the first-order modulation by both positive and negative allosteric modulators that act via benzodiazepine-binding
sites on GABAA receptors. It has effects on learning and memory, and demonstrates dose-dependent stress-reducing, anxiolytic,
sedative and hypnotic properties in a number of animal models.
A series of flavan-3-ol esters were synthesized as simpler analogs of EGCG (Fernandez et al., 2008). Fa131 (Fig. 6) proved to be a
nonsedating anxiolytic and a selective positive allosteric modulator of a2-containing GABAA receptors. Fa131 is the first positive
allosteric modulator to distinguish between a2- and a3-containing GABAA receptors, highlighting the potential of targeting
flumazenil-insensitive allosteric sites in the search for new anxio-selective drugs.
The structurally related Fa173 acts as a silent allosteric modulator, blocking the actions of Fa131 and of etomidate, loreclezole,
and low affinity diazepam, without influence on propofol, thiopental, and allopregnanolone (Fernandez et al., 2012). This suggests
that Fa131, etomidate, loreclezole, and low (nonflumazenil-sensitive) doses of diazepam all exert their positive modulatory effects
via a common or overlapping binding site that can be blocked by the silent allosteric modulator Fa173.
Among the many synthetic flavonoids that influence GABAA receptors are a series of 6-substituted flavones (Hanrahan et al.,
2015). These illustrate that highly structurally similar flavones can act as flumazenil-sensitive and flumazenil-insensitive positive
allosteric modulators, silent allosteric modulators, and negative allosteric modulators.
These and other studies have identified the presence of multiple sites on GABAA receptors at which a variety of flavonoids can act
as modulators. The sites include ones that are insensitive to the classical benzodiazepine silent allosteric modulator flumazenil and
are described as low affinity benzodiazepine sites. Perhaps, these would be more appropriately described as flavonoid sites as they
appear to be activated by numerous natural and synthetic flavonoids (Hinton et al., 2017).
to stress. Sex differences observed in the GABAergic neurotransmitter system following acute stress indicate the involvement of
gonadal steroids (Skilbeck et al., 2010).
The essential role for GABA in stress is well established, and the GABAergic system represents an important modifiable system for
regulating stress and anxiety. In addition to central nervous system regulation, GABA modulates stress via the fast acting sympatho-
adrenal-medullary (SAM) system, as part of the autonomic nervous system, and the slower acting hypothalamic–pituitary–adrenal
(HPA) axis.
Endogenous neurosteroids (Fig. 7) such as 3a-hydroxy-5a-pregnan-20-one (allopregnanolone, or 3a,5a-THP), synthesized from
progesterone, and 3a,21-dihydroxy-5a-pregnan-20-one (allotetrahydrodeoxycorticosterone, or 3a,5a-THDOC), synthesized from
corticosterone, are also known to be potent positive modulators of GABAA receptors (Hosie et al., 2009). These neurosteroids
modulate many GABAA receptor isoforms including combinations of ab, abg, and abd, with apparently greater potency at abd
receptor types (Lambert et al., 2009). It is likely that multiple binding sites for steroids exist on the GABAA receptor complex. These
neurosteroids can also be synthesized from cholesterol de novo in the brain during stress (Barbaccia et al., 2001; Higashi et al.,
2005). Synthetic steroids, including anesthetics such as alfaxalone and ganaxolone (Belelli and Lambert, 2005), also act as allosteric
modulators of the GABAA receptor.
Glucocorticoids, in addition to their genomic mechanism of action via intracellular glucocorticoid receptors, also have
nongenomic effects through modulation of GABAA receptors (Purdy et al., 1991). Cortisol and cortisone act as bi-directional
modulators of agonist binding and GABA function at GABAA receptors, with enhancement of agonist binding and GABA-mediated
response at low concentrations (pM–nM) and inhibition at higher concentrations (nM–mM) (Ong et al., 1987).
Acute stress in rodents has been shown to induce rapid changes in the GABAergic system. The number of functional binding sites
for GABA following a 3 min swim stress in mice was altered in opposite directions in males and females. These large changes were
rapid in onset but not sustained. This suggests a mechanism for rapid GABAergic plasticity possibly via receptor trafficking or
changes in endogenous GABAergic substances (Skilbeck et al., 2010).
Under chronic stress conditions it appears that neurosteroid concentrations decrease (Serra et al., 2000), while GABAA receptor
expression and function is also altered (Skilbeck et al., 2010, 2018), possibly contributing to disinhibition of the HPA axis and well-
documented elevated glucocorticoid concentrations following chronic stress.
Neurosteroids have been shown to enhance tonic GABAergic inhibition mediated by receptors containing the d subunit (Belelli
and Lambert, 2005). Chronic stress in adulthood decreases d subunit mRNA in the paraventricular nucleus of the hypothalamus
(Verkuyl et al., 2004) and, coupled with acute corticosteroid exposure, is found to increase a1 subunit mRNA in dentate gyrus
granule cells (Qin et al., 2004). In a recent investigation of early life conditioning impacts on GABAA receptor subunit expression, it
was shown that early life environment affects the regionally-dependent developmental subunit switch from a2 to a1 dominance,
and early life stress exaggerates this switch such that an increase in a1:a2 ratio occurred in stressed animals compared to the normal
condition in regions of the brain known to be involved in stress response such as the hippocampal dentate gyrus (Skilbeck et al.,
2018). This region thus represents a point of convergence for the impact of chronic stress on GABAergic regulation, its role in
neuropsychiatric disease development, and the potential role for neurosteroids in this response.
Given the important role of steroids in stress, and the essential role of stress in manifestation of a number of neuropsychiatric
disorders, including depression, anxiety and schizophrenia, chronic deregulation of steroid modulation of GABAA receptors is
thought to contribute to pathologies underlying such disorders (Cullinan et al., 2008). Some neurosteroids have been investigated
for their roles and potential therapeutic benefits in neuropsychiatric illnesses where stress is known to be a contributor (Schule et al.,
2011; Shirayama et al., 2011).
Ethanol
The key ingredient of regularly consumed “alcohol” is ethanol. Behavioral effects of ethanol include myorelaxation, anxiolysis,
sedation, impaired cognitive function, and an anticonvulsant effect. At higher doses, it can cause motor incoordination, ataxia,
amnesia, hypnosis, and anesthesia, and eventually respiratory depression and coma. While ethanol is known to influence several
sites in the central nervous system, it is now well understood that its major action at low to moderate doses is to positively modulate
GABAA receptors (Howard et al., 2014). At higher doses, ethanol also influences glutamate, glycine, and acetylcholine receptors.
Moreover, GABAA receptors are implicated in alcohol dependence, with studies showing polymorphisms in a2 and b1 subunits
confer vulnerability to alcohol dependence (McCabe et al., 2017).
At low to moderate doses (about 1–20 mM blood ethanol, 0.004%–0.08%, up to 2 standard drinks in 1 h), ethanol acts on
GABAA receptors containing the d subunit, coupled with the a4 and a6 subunits. The extra-synaptically-located a4bd and a6bd
receptors have greater affinity for GABA than the synaptic GABAA receptors, and, as described earlier, have been shown to regulate
the tonic inhibition mediated by ambient extracellular GABA. Ethanol administration increases neurosteroid concentration in the
periphery and CNS, with effects dependent on dose and region examined (Weiner and Valenzuela, 2006). Ethanol administration is
also shown to promote local neurosteroidogenesis (Sanna et al., 2004). Thus, ethanol influences GABAA receptor function in a
variety of ways—it positively modulates certain GABAA receptors in various brain regions, it promotes neurosteroid synthesis, and
neurosteroids form an indirect mechanism for ethanol action at GABAA receptors, by potentiating the effects of ethanol. Induction
of neurosteroid synthesis may augment the effects of ethanol since neurosteroids bind to d-containing GABAA receptor subunits and
produce anxiolytic, sedative, and anesthetic effects themselves.
At doses that begin to cause sedation and motor incoordination (about 20–30 mM), ethanol acts on GABAA receptors contain-
ing the g2L subunit (Howard et al., 2014). Receptors containing these subunits, when coupled with an a1, a2, a3, or a5 subunit, are
important for some of the sedative, anxiolytic, myorelaxant, anticonvulsant, and amnestic effects of GABA activation. At anesthetic
doses (50–400 mM) ethanol acts on most GABAA receptors (Howard et al., 2014). Ethanol also appears to enhance presynaptic
GABA release in the amygdala, hippocampus, and cerebellum, which may also contribute to its effects (Weiner and
Valenzuela, 2006).
The well-characterized flux in neurosteroid synthesis and expression of d subunit-containing GABAA receptors under conditions
of stress, during the menstrual cycle, and in neuropsychiatric disorders may explain the sex differences observed in the effects of
ethanol between males and females, as well as the differing effects of ethanol observed at different phases in the menstrual cycle
(Jimenez et al., 2017).
GABAB Receptors
The concept of GABAB receptors arose out of studies by David Hill and Norman Bowery in 1981 on the binding of the GABAB
analog baclofen (Fig. 2) to rat brain membranes (Hill and Bowery, 1981). They described a receptor that “differs from the classical
GABA site as it is unaffected by recognized GABA antagonists such as bicuculline.” They went on to state “We propose to designate
the classical site as the GABAA and the novel site as the GABAB receptor.” Special issues of Advances in Pharmacology and
Neuropharmacology that contain many authoritative papers on GABAB receptors have been published in honor of Norman Bowery
(Enna and Blackburn, 2010; Crunelli et al., 2018).
GABAB receptors are G protein-coupled receptors, formed as heterodimers composed of GABAB1 and GABAB2 protein subunits
(Enna and Blackburn, 2010; Froestl, 2011). They are tetramers with two GABAB1 subunits in close proximity flanked on either side
by GABAB2 subunits. Two isoforms of GABAB1 are known. The heterodimers formed by GABAB1a/GABAB2 proteins mediate
presynaptic inhibition whereas those formed by GABAB1b/GABAB2 mediate postsynaptic inhibition. GABA, GABAB agonists and
antagonists bind to the Venus flytrap module in the N-terminal region of the GABAB1 protein, while the GABAB2 mediates G protein
coupling. They are members of the group of class C G protein-coupled receptors with structural similarity to the metabotropic
glutamate receptors. Some GABAB receptors are coupled to activation of certain Kþ channels, producing slow inhibitory synaptic
currents. Other GABAB receptors can decrease Ca2þ conductance, regulate inositol triphosphate production, and/or inhibit cyclic
AMP production. GABAB antagonists, such as phaclofen (Fig. 3), have been described as well as positive and negative allosteric
modulators (Froestl, 2011).
CGP36742 (Fig. 3, also known as SGS742) was first described as an orally active GABAB antagonist for the treatment of cognitive
impairment (Froestl et al., 2004). Positive allosteric modulators show promise to treat addiction (Filip et al., 2015). GABAB agonists
may influence a range of disorders including trigeminal neuralgia, cerebral palsy, and autism (Froestl, 2011).
GABA Transport
GABA is removed from the extrasynaptic environment by uptake via Naþ-dependent, high affinity GABA transporters into the
presynaptic terminal for re-release or into postsynaptic terminals and neighboring glial cells. Inhibitors of GABA transport may
prolong synaptic inhibition and act as anticonvulsants. The concentration gradients across membranes are large, with mM GABA
intracellularly and mM extracellularly. Several high affinity GABA transport proteins have been cloned (GAT1, GAT2, GAT3, and
BGT1), as well as a vesicular GABA transport protein (VGAT) representing important therapeutic targets (Schousboe et al., 2014;
Zhou and Danbolt, 2013).
GAT1 and GAT3 are the GABA transporters of major interest in the CNS. GAT1 is found predominately in GABAergic nerve
terminals where it recycles synaptically released GABA. GAT3 is found predominately in astrocytes where it maintains low
extracellular levels of GABA. GAT2 and BGT1 are expressed mainly in hepatocytes in the kidney and liver. The affinity of GABA
varies considerably with the reported Km values for the mouse isoforms being 8 mM for GAT1, 18 for GAT2, 0.8 for GAT3 and 80 for
BGT1. It is unlikely that BGT1 contributes to GABA inactivation.
The first therapeutically useful inhibitors of GABA transporters arose from studies on muscimol (Johnston, 2014; Krogsgaard-
Larsen et al., 2000). Structure–activity studies on analogs of muscimol led to the development of a series of nipecotic acid
derivatives of inhibitors of GABA transport, notably tiagabine (Fig. 8, Gabril), a GAT1 selective inhibitor that is anticonvulsant
and used in the treatment of epilepsy (Fig. 5). Tiagabine has profound side effects similar to those found in GAT1 knockout mice
(Schousboe et al., 2014; Zhou and Danbolt, 2013). It is the only GAT inhibitor approved for clinical use. Selective GAT3 inhibitors,
such as SNAP5114, are antinociceptive, acting by stimulation of GABAA and GABAB receptors in the spinal cord (Kataoka et al.,
2013). Novel highly selective GAT3 inhibitors have been developed (Damgaard et al., 2015) but there are as yet no reports of their
therapeutic properties. A GAT3 knockout mouse has been foreshadowed (Zhou and Danbolt, 2013) but no reports have emerged,
possibly as knocking out GAT3 may be lethal.
The vesicular transporter VGAT is important for the packing of synaptic vesicles with GABA, thereby determining the amount of
GABA released per vesicle (Van Liefferinge et al., 2013). No agents have been found that specifically inhibit VGAT although the
GABA aminotransferase inhibitor vigabatrin shows some activity. VGAT knockout mice are not viable. Potentially VGAT inhibitors
are a target for the treatment of epilepsy.
GABA Metabolism
GABA is metabolized intracellularly via the tricarboxylic acid cycle in mitochondria by GABA-aminotransferase (GABA-T) to
succinic semialdehyde then oxidized by succinic semialdehyde dehydrogenase to succinic acid.
The metabolic pathway 2-ketoglutarate—glutamate—GABA—succinate is known as the GABA shunt, a pathway which bypasses
part of the normal tricarboxylic cycle in brain. Up to 30% of the turnover of the tricarboxylic acid cycle in brain is via the GABA
shunt, illustrating the importance of GABA metabolism in the overall metabolism of the brain. Different pools of GABA with
different turnover rates and pool sizes are known to occur in the brain (Waagepetersen et al., 2003). Indeed, it is thought that only a
fraction of GABA in the brain is neurotransmitter GABA, with the remainder located in cell bodies as a metabolic pool. Inhibitors of
GABA metabolism can increase brain levels of GABA up to 10-fold and act as anticonvulsants. This provides evidence of the rapid
turnover of GABA in the brain.
The most well researched GABA-T inhibitor is g-vinyl-GABA (Fig. 8, Vigabatrin, Sabril) that is used as an anticonvulsant. It was
rationally designed as a suicide substrate binding irreversibly to the enzyme (Metcalf, 1979).
Although exogenous GABA is not generally considered to pass the blood–brain-barrier, orally administered GABA does have effects
that suggest it can alter brain function (Boonstra et al., 2015). GABA is an important constituent of most plants where it plays an
important role in plant metabolism and as a signaling molecule modulating anion flux (Rabbani et al., 2011). As such, GABA is
found in plant derived foodstuffs and herbal medicines. It occurs alongside numerous agents that can influence GABA function in
the brain, such as flavonoids (Hanrahan et al., 2015). A range of plant-derived anxiolytic medicines contains GABA modulating
agents (Savage et al., 2018).
GABA is widely available as a dietary supplement (Boonstra et al., 2015). Many people report that these supplements reduced
anxiety and improve sleep quality. Oral GABA has been shown to improve sleep (Yamatsu et al., 2016) and memory (Thanapree-
dawat et al., 2013). GABA enriched chocolate has a stress reducing effect (Nakamura et al., 2009). The levels of GABA in tea may be
considerably enhanced by anaerobic fermentation. Such GABA tea has been reported to reduce blood pressure, promote sleep, and
reduce depression (Teng et al., 2017; Zhao et al., 2015).
These effects of exogenous GABA may reflect actions on GABA receptors in the peripheral nervous system and interactions with
other agents that influence GABA receptors. Endogenous GABA is important in gastrointestinal function (Auteri et al., 2015) and the
effects of exogenous GABA may involve the enteric nervous system (Boonstra et al., 2015).
GABA occurs in high levels in insulin-producing b-cells of the pancreas. These cells release GABA to act on GABA receptors on
neighboring islet a-cells to inhibit the secretion of glucagon that counteracts the effects of insulin (Feng et al., 2017). These cells may
represent another site of action of exogenous GABA.
GABA is an important neurotransmitter in insects and insect GABA receptors are key targets for insecticides (Casida and Durkin,
2015). Whereas insect GABA receptors do differ from mammalian GABA receptors sufficiently to enable insecticides selectively
targeting insects to be produced, such as pyrethroids, toxicity to honey bees may be a problem (Oliver et al., 2015).
Conclusion
For such a simple molecule, GABA has many and varied complex functions. This research module concentrates on the role of GABA
as the major neurotransmitter in the brain. It emphasizes the range of agents that can influence the action of GABA as a
neurotransmitter and the effects that such agents can have on brain function. Agents that have increasingly selective actions on
GABA function are targets for the development of new drugs.
Acknowledgment
The authors are grateful to Dr. Ken Mewett for his helpful comments.
References
Abselhalim A, Chebib M, Aburjai T, Johnston GAR, and Hanrahan J (2014) GABAA receptor modulation by compounds isolated from Salvia triloba L. Advances in Biological Chemistry
4: 148–159.
Auteri M, Zizzo MG, and Serio R (2015) The GABAergic system and the gastrointestinal physiopathology. Current Pharmaceutical Design 21: 4996–5016.
Bakas T, Van Nieuwenhuijzen PS, Devenish SO, et al. (2017) The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacological Research
119: 358–370.
Barbaccia ML, Serra M, Purdy RH, and Biggio G (2001) Stress and neuroactive steroids. International Review of Neurobiology 46: 243–272.
Belelli D and Lambert JJ (2005) Neurosteroids: Endogenous regulators of the GABA(A) receptor. Nature Reviews Neuroscience 6: 565–575.
Belelli D, Harrison NL, Maguire J, et al. (2009) Extrasynaptic GABAA receptors: Form, pharmacology, and function. Journal of Neuroscience 29: 12757–12763.
Boddum K, Frølund B, and Kristiansen U (2014) The GABAA antagonist DPP-4-PIOL selectively antagonises tonic over phasic GABAergic currents in dentate gyrus granule cells.
Neurochemical Research 39: 2078–2084.
Boonstra E, De Kleijn R, Colzato LS, et al. (2015) Neurotransmitters as food supplements: The effects of GABA on brain and behavior. Frontiers in Psychology 6: 1520.
Bowery NG and Smart TG (2006) GABA and glycine as neurotransmitters: A brief history. British Journal of Pharmacology 147: S109–S119. Suppl 1.
Campbell EL, Chebib M, and Johnston GAR (2004) The dietary flavonoids apigenin and ()-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by
GABA of recombinant GABAA receptors. Biochemical Pharmacology 68: 1631–1638.
Casida JE and Durkin KA (2015) Novel GABA receptor pesticide targets. Pesticide Biochemistry and Physiology 121: 22–30.
Changeux JP (2013) The concept of allosteric modulation: An overview. Drug Discovery Today: Technologies 10: e223–e228.
Chebib M, Hinton T, Schmid KL, et al. (2009) Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory. The Journal of
Pharmacology and Experimental Therapeutics 328: 448–457.
Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: Novel targets for drug discovery. Nature Reviews Drug Discovery 1: 198–210.
Crestani F and Rudolph U (2015) Behavioral functions of GABAA receptor subtypes—The Zurich experience. Advances in Pharmacology 72: 37–51.
Crunelli V, Enna SJ, and Bettler B (2018) A special issue dedicated by Norman G. Bowery. Neuropharmacology 136: 1–158.
Cullinan WE, Ziegler DR, and Herman JP (2008) Functional role of local GABAergic influences on the HPA axis. Brain Structure & Function 213: 63–72.
Damgaard M, Al-Khawaja A, Vogensen SB, et al. (2015) Identification of the first highly subtype-selective inhibitor of human GABA transporter GAT3. ACS Chemical Neuroscience
6: 1591–1599.
Darmani G, Zipser CM, Bohmer GM, et al. (2016) Effects of the selective alpha5-GABAAR antagonist S44819 on excitability in the human brain: A TMS-EMG and TMS-EEG phase
I study. Journal of Neuroscience 36: 12312–12320.
Davis AM, Penschuck S, Fritschy JM, and Mccarthy MM (2000) Developmental switch in the expression of GABA(A) receptor subunits alpha(1) and alpha(2) in the hypothalamus and
limbic system of the rat. Developmental Brain Research 119: 127–138.
Distler MG, Plant LD, Sokoloff G, et al. (2012) Glyoxalase 1 increases anxiety by reducing GABA(A) receptor agonist methylglyoxal. Journal of Clinical Investigation 122: 2306–2315.
Doshina A, Gourgue F, Onizuka M, et al. (2017) Cortical cells reveal APP as a new player in the regulation of GABAergic neurotransmission. Scientific Reports 7: 370.
Drew CA, Johnston GAR, and Weatherby RP (1984) Bicuculline-insensitive GABA receptors: Studies on the binding of ()-baclofen to rat cerebellar membranes. Neuroscience Letters
52: 317–321.
Enna SJ and Blackburn TP (2010) GABAB receptor pharmacology: A tribute to Norman Bowery. Advances in Pharmacology 58: XV–XVI.
Etherington LA, Mihalik B, Palvolgyi A, et al. (2017) Selective inhibition of extra-synaptic alpha 5-GABA(A) receptors by S44819, a new therapeutic agent. Neuropharmacology
125: 353–364.
Farzampour Z, Reimer RJ, and Huguenard J (2015) Endozepines. Advances in Pharmacology 72: 147–164.
Feng AL, Xiang YY, Gui L, et al. (2017) Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes. Diabetologia 60: 1033–1042.
Fernandez SP, Mewett KN, Hanrahan JR, Chebib M, and Johnston GA (2008) Flavan-3-ol derivatives are positive modulators of GABAA receptors with higher efficacy for the alpha(2)
subtype and anxiolytic action in mice. Neuropharmacology 55: 900–907.
Fernandez SP, Karim N, Mewett KN, et al. (2012) Flavan-3-ol esters: New agents for exploring modulatory sites on GABAA receptors. British Journal of Pharmacology 165: 965–977.
Filip M, Frankowska M, Sadakierska-Chudy A, et al. (2015) GABAB receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators.
Neuropharmacology 88: 36–47.
Fritschy JM (2015) Significance of GABA(A) receptor heterogeneity: Clues from developing neurons. Advances in Pharmacology 73: 13–39.
Froestl W (2011) An historical perspective on GABAergic drugs. Future Medicinal Chemistry 3: 163–175.
Froestl W, Gallagher M, Jenkins H, et al. (2004) SGS742: The first GABA(B) receptor antagonist in clinical trials. Biochemical Pharmacology 68: 1479–1487.
Furukawa M, Tsukahara T, Tomita K, et al. (2017) Neonatal maternal separation delays the GABA excitatory-to-inhibitory functional switch by inhibiting KCC2 expression. Biochemical
and Biophysical Research Communications 493: 1243–1249.
Gao H and Smith BN (2010) Zolpidem modulation of phasic and tonic GABA currents in the rat dorsal motor nucleus of the vagus. Neuropharmacology 58: 1220–1227.
Hanrahan JR, Chebib M, and Johnston GAR (2015) Interactions of flavonoids with ionotropic GABA receptors. Advances in Pharmacology 72: 189–200.
Heaulme M, Chambion JP, Leyris R, et al. (1986) Biochemical characterization of the interaction of three pyridazinyl-GABA derivatives with the GABAA receptor site. Brain Research
384: 224–231.
Higashi T, Takido N, and Shimada K (2005) Analysis of stress-induced changes in neurosteroid levels in rat brains using liquid chromatography-electron capture atmospheric pressure
chemical ionization-mass spectrometry. Steroids 70: 1–11. Studies on neurosteroids XVII.
Hill DR and Bowery NG (1981) 3H-baclofen and 3H-GABA bind to bicuculline insensitive GABA sites in rat brain. Nature 290: 149–152.
Hinton T, Hanrahan J, and Johnston GAR (2017) Flavonoid actions on receptors for the inhibitory neurotransmitter GABA. In: Justino J (ed.) Flavonoids—From biosynthesis to human
health, pp. 335–349. Croatia: InTech.
Hosie AM, Clarke L, Da Silva H, and Smart TG (2009) Conserved site for neurosteroid modulation of GABA A receptors. Neuropharmacology 56: 149–154.
Howard RJ, Trudell JR, and Harris RA (2014) Seeking structural specificity: Direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics.
Pharmacological Reviews 66: 396–412.
Hunt P and Clementsjewery S (1981) A steroid derivative, R-5135, antagonizes the GABA-benzodiazepine receptor interaction. Neuropharmacology 20: 357–361.
Iqbal F, Ellwood R, Mortensen M, Smart TG, and Baker JR (2011) Synthesis and evaluation of highly potent GABAA receptor antagonists based on gabazine (SR-95531). Bioorganic &
Medicinal Chemistry Letters 21: 4252–4254.
Jimenez VA, Walter NA, Jensen JP, et al. (2017) Relationship between menstrual cycle phase, neurosteroid concentration and ethanol self-administration in rhesus macaques.
Alcoholism, Clinical and Experimental Research 41: 112A.
Johnston GAR (2013) Advantages of an antagonist: Bicuculline and other GABA antagonists. British Journal of Pharmacology 169: 328–336.
Johnston GAR (2014) Muscimol as an ionotropic GABA receptor agonist. Neurochemical Research 39: 1942–1947.
Johnston GAR (2016) Unsaturated analogues of the neurotransmitter GABA: trans-4-aminocrotonic, cis-4-aminocrotonic and 4-aminotetrolic acids. Neurochemical Research
41: 476–480.
Johnston GAR, Chebib M, Hanrahan JR, and Mewett KN (2003) GABAC receptors as drug targets. Current Drug Targets. CNS and Neurological Disorders 2: 260–268.
Kataoka K, Hara K, Haranishi Y, Terada T, and Sata T (2013) The antinociceptive effect of SNAP5114, a gamma-aminobutyric acid transporter-3 inhibitor, in rat experimental pain
models. Anesthesia and Analgesia 116: 1162–1169.
Kavvadias D, Sand P, Youdim KA, et al. (2004) The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits
anticonvulsive effects. British Journal of Pharmacology 142: 811–820.
Koch U and Magnusson AK (2009) Unconventional GABA release: Mechanisms and function. Current Opinion in Neurobiology 19: 305–310.
Krall J, Balle T, Krogsgaard-Larsen N, et al. (2015) GABAA receptor partial agonists and antagonists: Structure, binding mode, and pharmacology. Advances in Pharmacology
72: 201–227.
Krogsgaard-Larsen P, Frølund B, and Frydenvang K (2000) GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects. Current Pharmaceutical Design
6: 1193–1209.
Krogsgaard-Larsen P, Frølund B, Liljefors T, and Ebert B (2004) GABAA agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic.
Biochemical Pharmacology 68: 1573–1580.
Lambert JJ, Cooper MA, Simmons RD, Weir CJ, and Belelli D (2009) Neurosteroids: Endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology 34: S48–S58.
Suppl 1.
Maldifassi MC, Baur R, and Sigel E (2016) Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital.
Neuropharmacology 105: 207–214.
Manayi A, Nabavi SM, Daglia M, and Jafari S (2016) Natural terpenoids as a promising source for modulation of GABAergic system and treatment of neurological diseases.
Pharmacological Reports 68: 671–679.
McCabe WA, Way MJ, Ruparelia K, et al. (2017) Genetic variation in GABR beta 1 and the risk for developing alcohol dependence. Psychiatric Genetics 27: 110–115.
McMurray KMJ, Ramaker MJ, Barkley-Levenson AM, et al. (2018) Identification of a novel, fast-acting GABAergic antidepressant. Molecular Psychiatry 23: 384–391.
Medina JH, Viola H, Wolfman C, et al. (1997) Overview—Flavonoids–A new family of benzodiazepine receptor ligands. Neurochemical Research 22: 419–425.
Mesce KA (2002) Metamodulation of the biogenic amines: Second-order modulation by steroid hormones and amine cocktails. Brain, Behavior and Evolution 60: 339–349.
Metcalf BW (1979) Inhibitors of GABA metabolism. Biochemical Pharmacology 28: 1705–1712.
Mitoma H, Manto M, and Hampe CS (2017) Pathogenic roles of glutamic acid decarboxylase 65 autoantibodies in cerebellar ataxias. Journal of Immunology Research 2017: 2913297.
Möhler H (2015) The legacy of the benzodiazepine receptor: From flumazenil to enhancing cognition in Down syndrome and social interaction in autism. Advances in Pharmacology
72: 1–36.
Mortensen M, Ebert B, Wafford K, and Smart TG (2010) Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABA(A) receptors. Journal of Physiology (London)
588: 1251–1268.
Mortensen M, Iqbal F, Pandurangan AP, et al. (2014) Photo-antagonism of the GABAA receptor. Nature Communications 5.
Murata Y, Woodward RM, Miledi R, and Overman LE (1996) The first selective antagonist for a GABAC receptor. Bioorganic & Medicinal Chemistry Letters 6: 2073–2076.
Naffaa MM, Hung S, Chebib M, Johnston GAR, and Hanrahan JR (2017) GABA-r receptors: Distinctive functions and molecular pharmacology. British Journal of Pharmacology
174: 1881–1894.
Nakamura H, Takishima T, Kometani T, and Yokogoshi H (2009) Psychological stress-reducing effect of chocolate enriched with gamma-aminobutyric acid (GABA) in humans:
Assessment of stress using heart rate variability and salivary chromogranin A. International Journal of Food Sciences and Nutrition 60: 106–113.
Ng CK, Kim HL, Gavande N, et al. (2011) Medicinal chemistry of r GABAC receptors. Future Medicinal Chemistry 3: 197–209.
Ng CC, Duke RK, Hinton T, and Johnston GAR (2017) Effects of bilobalide, ginkgolide B and picrotoxinin on GABA(A) receptor modulation by structurally diverse positive modulators.
European Journal of Pharmacology 806: 83–90.
Nothdurfter C, Baghai TC, Schule C, and Rupprecht R (2012) Translocator protein (18 kDa) (TSPO) as a therapeutic target for anxiety and neurologic disorders. European Archives of
Psychiatry and Clinical Neuroscience 262: S107–S112.
Oliver CJ, Softley S, Williamson SM, Stevenson PC, and Wright GA (2015) Pyrethroids and nectar toxins have subtle effects on the motor function, grooming and wing fanning
behaviour of honeybees (Apis mellifera). PLoS One 10: 12.
Olsen RW (2015) Allosteric ligands and their binding sites define gamma-aminobutyric acid (GABA) type A receptor subtypes. Advances in Pharmacology 73: 167–202.
Olsen RW, Ban M, Miller T, and Johnston GAR (1975) Chemical instability of the GABA antagonist bicuculline under physiological conditions. Brain Research 98: 383–387.
Ong J, Kerr DI, and Johnston GAR (1987) Cortisol: A potent biphasic modulator at GABAA-receptor complexes in the guinea pig isolated ileum. Neuroscience Letters 82: 101–106.
Purdy RH, Morrow AL, Moore PH, and Paul SM (1991) Stress-induced elevations of g-aminobutyric acid type A receptor-active steroids in the rat brain. Proceedings of the National
Academy of Sciences of the United States of America 88: 4553–4557.
Qin YJ, Karst H, and Joels M (2004) Chronic unpredictable stress alters gene expression in rat single dentate granule cells. Journal of Neurochemistry 89: 364–374.
Rabbani N, Godfrey L, Xue MZ, et al. (2011) Glycation of LDL by methylglyoxal increases arterial atherogenicity a possible contributor to increased risk of cardiovascular disease in
diabetes. Diabetes 60: 1973–1980.
Ribeiro JA and Sebastiao AM (2010) Modulation and metamodulation of synapses by adenosine. Acta Physiologica 199: 161–169.
Rudolph U and Möhler H (2014) GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annual Review of Pharmacology
and Toxicology 54: 483–507.
Sanna E, Talani G, Busonero F, et al. (2004) Brain steroidogenesis mediates ethanol modulation of GABA(A) receptor activity in rat hippocampus. Journal of Neuroscience
24: 6521–6530.
Savage K, Firth J, Stough C, and Sarris J (2018) GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence. Phytotherapy Research
32: 3–18.
Schousboe A, Madsen KK, Barker-Haliski ML, and White HS (2014) The GABA synapse as a target for antiepileptic drugs: A historical overview focused on GABA transporters.
Neurochemical Research 39: 1980–1987.
Schule C, Eser D, Baghai TC, et al. (2011) Neuroactive steroids in affective disorders: Target for novel antidepressant or anxiolytic drugs? Neuroscience 191: 55–77.
Serra M, Pisu MG, Littera M, et al. (2000) Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. Journal of
Neurochemistry 75: 732–740.
Shirayama Y, Muneoka K, Fukumoto M, et al. (2011) Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal
cortex, produce antidepressant effects on the learned helplessness rats. Hippocampus 21: 1105–1113.
Sigel E and Steinmann ME (2012) Structure, function, and modulation of GABAA receptors. Journal of Biological Chemistry 287: 40224–40231.
Sigel E, Baur R, Racz I, et al. (2011) The major central endocannabinoid directly acts at GABA(A) receptors. Proceedings of the National Academy of Sciences of the United States of
America 108: 18150–18155.
Simmonds MA and Turner JP (1985) Antagonism of inhibitory amino acids by the steroid derivative RU5135. British Journal of Pharmacology 84: 631–635.
Skilbeck KJ, Johnston GAR, and Hinton T (2010) Stress and GABA receptors. Journal of Neurochemistry 112: 1115–1130.
Skilbeck KJ, Hinton T, and Johnston GAR (2018) Long-lasting effects of early-life intervention in mice on adulthood behaviour, GABAA receptor subunit expression and synaptic
clustering. Pharmacological Research 128: 179–189.
Skolnick P (2012) Anxioselective anxiolytics: On a quest for the holy grail. Trends in Pharmacological Sciences 33: 611–620.
Teng J, Zhou W, Zeng Z, et al. (2017) Quality components and antidepressant-like effects of GABA green tea. Food & Function 8: 3311–3318.
Thanapreedawat P, Kobayashi H, Inui N, et al. (2013) GABA affects novel object recognition memory and working memory in rats. Journal of Nutritional Science and Vitaminology
59: 152–157.
Thompson SA, Wheat L, Brown NA, et al. (2004) Salicylidene salicylhydrazide, a selective inhibitor of b1-containing GABAA receptors. British Journal of Pharmacology 142: 97–106.
Van Liefferinge J, Massie A, Portelli J, Di Giovanni G, and Smolders I (2013) Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy? Frontiers
in Cellular Neuroscience 7: 24.
Verkuyl JM, Hemby SE, and Joels M (2004) Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. European Journal
of Neuroscience 20: 1665–1673.
Vignes M, Maurice T, Lante F, et al. (2006) Anxiolytic properties of green tea polyphenol ()-epigallocatechin gallate (EGCG). Brain Research 1110: 102–115.
Waagepetersen HS, Sonnewald U, and Schousboe A (1999) The GABA paradox: Multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent [Review]. Journal of
Neurochemistry 73: 1335–1342.
Waagepetersen HS, Sonnewald U, and Schousboe A (2003) Compartmentation of glutamine, glutamate, and GABA metabolism in neurons and astrocytes: Functional implications. The
Neuroscientist 9: 398–403.
Walters RJ, Hadley SH, Morris KDW, and Amin J (2000) Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms. Nature Neuroscience 3: 1274–1281.
Weiner JL and Valenzuela CF (2006) Ethanol modulation of GABAergic transmission: The view from the slice. Pharmacology & Therapeutics 111: 533–554.
Yamatsu A, Yamashita Y, Pandharipande T, Maru I, and Kim M (2016) Effect of oral gamma-aminobutyric acid (GABA) administration on sleep and its absorption in humans. Food
Science and Biotechnology 25: 547–551.
Yoon BE and Lee CJ (2014) GABA as a rising gliotransmitter. Frontiers in Neural Circuits 8: 141.
Zhao WF, Li Y, Ma W, Ge YZ, and Huang YH (2015) A study on quality components and sleep-promoting effects of GABA black tea. Food & Function 6: 3393–3398.
Zhou Y and Danbolt NC (2013) GABA and glutamate transporters in brain. Frontiers in Endocrinology 4: 165.