Targeting GABA to Cure Anxiety Disorder in Various Methods

Yihui Lu

†

Jiayi Yuan

†

and Xichen Zhang

†

Environmental and Life Sciences Faculty University of Southampton, Southampton, U.K.

Qingdao Chengyang No.1 Senior High School, Qingdao, China

Shanghai Shangde Experimental School, Shanghai, China

†

These authors contributed equally

Keywords: GABA, GABAA Receptor, Benzodiazepine, GABAB Receptor, Anxiety Disorder.

Abstract: The number of people suffering from anxiety disorders has risen sharply in recent years. Gamma-

aminobutyric acid (GABA) is a neurotransmitter in the central nervous system that inhibits (prevents) nerve

activity by restricting nerve transmission. A large number of studies have shown that low GABA levels or

GABA system dysfunction can cause anxiety. This article mainly summarizes the treatment and mechanism

of anxiety disorders for GABA metabolic uptake, GABAA receptor, and GABAB receptor. The metabolic

process of GABA was outlined, by using drugs that increase the expression of GAD, inhibit GABA-T, and

block GAT to increased the content of GABA and treat anxiety. The structure of GABAA receptors and how

benzodiazepine targets GABAA receptors to treat anxiety disorders were detailed. Finally, anxiety disorders

can be treated by GABAB receptor agonist baclofen and positive allosteric modulators (PAMs).

1 INTRODUCTION

Anxiety is a common unpleasant emotional state

marked by emotions of fear and dread, as well as

distinct physical, cognitive, and behavioral

symptoms. Anxiety is a normal element of one's

behavioral repertoire, and it can be useful as a

protective mechanism for increasing awareness and

response to unexpected situations. However, when it

is overly intense or frequent, or when it occurs in

inappropriate situations, it can interfere with regular

functioning and thus be called abnormal (Roy-Byrne,

2005). The people who are in this state are suffering

from an anxiety disorder. Anxiety disorder is a major

mental health problem that affects people all over the

world and the proportion of people who are suffering

from this disease are increasing. In a 2020 survey, 62

percent of respondents said they were anxious in

some way (Team 2021). And the proportion of those

who are suffering from an anxiety disorder is

increasing year after year. The global prevalence of

all mental disorders increased by 50% between 1990

and 2013, from 416 million to 615 million persons

https://orcid.org/0000-0003-3963-7140

https://orcid.org/0000-0001-8315-7609

https://orcid.org/0000-0003-2712-1091

(World Health Organizations 2021). Besides,

Anxiety disorders impacted around 273 million

people worldwide in 2010. In 2017, an estimated 264

million people worldwide suffered from anxiety

(Figure 1). Thus, there are such a large number of

people are struggling with this disease, our research

aims to provide a great number of meaningful

methods to relieve symptoms to some extent.

Figure 1: The number of mental disorder patients (World

Health Organizations, 2021).

Gamma-aminobutyric acid (GABA), which is

found in more than a third of central nervous system

366

Lu, Y., Yuan, J. and Zhang, X.

Targeting GABA to Cure Anxiety Disorder in Various Methods.

DOI: 10.5220/0011208900003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 366-373

ISBN: 978-989-758-595-1

(CNS) synapses, is one of the most widely distributed

neurotransmitters in the brain (Peter P Roy-Byrne

2021). The etiology of anxiety disorders is related to

changes in the GABA system. Allosteric sites on the

GABA receptor allow for precise modulation of the

level of inhibition of neurons in the amygdala, and

these sites are the molecular targets of the most

common types of anxiolytic medicines (Gauthier

2015).

To explain the content of GABA and the

treatment of anxiety, we first detailed the metabolic

process of GABA by employing medications that

boost the expression of GAD, inhibit GABA-T, and

block GAT. The structure of GABAA receptors was

then discussed, as well as how benzodiazepines target

GABAA receptors to treat anxiety disorders. Finally,

anxiety disorders can be treated using the GABAB

receptor agonist baclofen and positive reinforcement.

2 GABA METABOLISM

GABA transport, sequestration, synthesis, and

degradation are all mediated by various specific

molecular pathways (Roth 2021). GABA metabolism

and uptake both play a role in the factors that

influence anxiety pathogenesis (Kalueff, 2007).

The enzyme glutamic acid decarboxylase (GAD)

and the cofactor pyridoxal phosphate are used to

convert glutamate, the principal excitatory

neurotransmitter, into GABA in the GABAergic

neurons of the central nervous system. Only cells that

employ GABA as a neurotransmitter produce GAD.

GABA is packaged into vesicles by vesicle GABA

transporters (VGAT), released into the synaptic cleft,

and diffused across the cleft to the target receptors

located on the postsynaptic surface when the

presynaptic neuron is depolarized. Furthermore,

Presynaptic terminals and surrounding glial cells can

resorb GABA released into the synapse cleft for a

variety of objectives. Membrane GABA transporters

(GAT) allow GABA to be re-used in presynaptic

terminals, however GABA in glial cells is converted

to succinic semialdehyde by GABA-T and cannot be

re-synthesised in this compartment because glia lack

GAD. Through a circuitous route that involves the

Krebs cycle, GABA can eventually be recovered

from this source. GABA is transformed to glutamine

in glia by the GABA shunt, which subsequently

transports glutamine back to presynaptic neurons,

where glutamine is converted to glutamate by

glutaminase. Anxiety is dependent on GABA

metabolism, which may be disrupted in the

pathophysiology (Siegel 1999).

2.1 Glutamic Acid Decarboxylase

The enzyme glutamic acid decarboxylase (GAD) is

responsible for converting glutamate to GABA. GAD

comes in two molecular forms in the mammalian

brain: Glutamic acid decarboxylase 67 (GAD67) and

Glutamic acid decarboxylase (GAD65), which are

produced by two independently regulated genes,

GAD1 and GAD2, respectively (Tillakaratne, 1995)

(Hettema 2006). In terms of intraneuronal expression,

GAD65 appears to be more restricted to axon

terminals, whereas GAD67 appears to be more

equally distributed throughout the neuron.

Furthermore, the active cofactor-bound holoenzyme

form of GAD67 makes up nearly all of the enzyme,

whereas majority of GAD65 is found as a reserve

pool of inactive apoenzyme. One study suggests that

acute stress may enhance GAD67 production,

whereas chronic stress may increase GAD65

availability (Hettema 2006).

Mice missing a short 65-kDa GAD isoform

(GAD65), which is responsible for fine-tuning

GABAergic neurotransmission, GABA levels were

lower and anxiety levels were higher, whereas AD

reboxetine increased GAD65 expression in the

septum of stressed rats. Recent research has

discovered a relationship has been discovered

between a GAD65 gene polymorphism and anxiety-

related behavioral inhibition in childre, as well as

lower levels of GAD65 and GAD67 in the prefrontal

cortex and cerebellum in depressed people (Kalueff

2007). In human studies, neurotic patients and those

with mood disorders showed lower GAD plasma

activity. In a small family-based study of children,

researchers discovered a small link between GAD2

and behavioral inhibition, and anxiety-related traits

(Hettema 2006). Therefore, a decrease in GAD level

will result in less synthesis of GABA, which will lead

to increased anxiety.

2.2 GABA Transaminase

Another important enzyme in GABA turnover is

GABA transaminase (GABA-T), which catabolizes

GABA (Kalueff 2007). GABA-T inhibition increases

brain levels of the main inhibitory neurotransmitter

GABA, which has been linked to a range of

functional consequences, including behavioral

alterations (Sherif 1995). Its inhibitors, such as

Vigabatrin (gamma-vinyl GABA, GVG), can raise

brain GABA levels by irreversibly blocking GABA-

T. In the plus-maze test, treatment with vigabatrin at

a dose of 250 mg/kg, i.p. lowered anxiety levels in

both groups of differentially housed rats

Targeting GABA to Cure Anxiety Disorder in Various Methods

367

(Tillakaratne, 1995). Inhibiting GABA-T, elevating

brain GABA levels, producing anxiolytic-like effects

in animals, and modulating glutamate and

catecholamine neurotransmission are all effects of the

AD phenelzine (In humans, it is beneficial in the

treatment of social anxiety and panic disorders)

(Kalueff 2007). In various experimental models,

phenylethylidenehydrazine (PEH), an derivative of

the monoamine oxidase inhibitor beta-phenylmethyl

hydrazine (phenelzine), which inhibits the gamma-

aminobutyric acid (GABA) catabolic enzyme

GABA-transaminase and elevates GABA levels in

the brain and has strong anxiolytic properties (Duffy

2004).

2.3 GABA Transporter

GABA transporters (GATs) are important molecules

in the transfer of GABA and are found on the

membrane of cells. At the synapse, GATs can

regulate the duration and intensity of GABAergic

activity by reabsorbing GABA. GAT1, GAT2,

GAT3, and GAT4 are among the GABA transporter

subtypes discovered. GAT1 is the most common

subtype in the brain, and it can be found in both

synaptic and extrasynaptic sites (Liu 2007). It's also

in charge of maintaining 75 percent of synaptic

GABA concentration and delivering it to GABAA

receptors to initiate receptor-mediated postsynaptic

neuron inhibition. GAT1 is largely involved in

GABA binding and transport from the cytoplasm to

the extracellular space (reverse mode) and back

(forward mode). As a result, if GAT1 is

malfunctioning, communication with postsynaptic

GABA receptors may be delayed (Zafar 2018).

GAT1 deficiency results in increased extracellular

GABA levels and GABAA receptor overactivation.

Tremor, ataxia, and nervousness are all symptoms of

GAT1 deficiency, according to behavioral tests.

GAT1 is involved in the development of anxiety

disorders, according to several behavioral tasks such

as the tail-suspension test, forced swim test, and

open-field test. Tiagabine hydrochloride is a selective

GABA reuptake inhibitor that blocks GAT1 and

hence raises GABA tone. It is used to treat anxiety

disorders. For decades, GAT1 has been recognized as

a potential therapeutic target due to its critical role in

the GABAergic transport mechanism (Liu 2007).

2.4 Neuropeptide

Neuropeptides are small proteins that operate as

neuronal signaling molecules and have a role in a

variety of brain functions, including analgesia,

reward systems, social behaviors, learning, and

memory (Garakani 2020). It's also important to

consider neuropeptides' role in modulating

GABAergic function and anxiety/depression

interplay. Melatonin, for example, has been shown in

animals to have both anxiolytic and anti-properties

(Kalueff 2007). Melatonin improved GABAergic

inhibitory transmission by increasing the amplitude

and frequency of GABAergic mIPSCs. As a result,

we've discovered that melatonin boosts the

GABAergic system's performance (Cheng 2021).

Cholecystokinin antagonists are neuropeptides that

regulate the GABAergic system and is implicated in

both anxiety pathogenesis and treatment, have been

found to have similar properties (Kalueff 2007).

Oxytocin has been associated to high anxiety in

healthy individuals and has been proven to have a

good influence on emotion modulation in healthy

adults. Animal research imply that oxytocin has

anxiolytic qualities, however human studies suggest

that oxytocin can produce acute anxiety. In animal

models, arginine vasopressin (AVP) has been linked

to anxiety, anxiolytic properties may be found in

vasopressin V1a and V1b receptor antagonists.

Despite the fact that neuropeptides appear to be a

promising new therapy option for anxiety disorders,

no specific treatment candidates have been identified

(Garakani 2020).

3 GABAA RECEPTOR

The GABAA receptor is one of the most common

types of receptor for the inhibitory neurotransmitter

y-aminobutyric acid (GABA) (OLSEN, Tobin 1990).

GABAA receptors are made up of five protein

subunits that bridge a lipid bilayer to produce a

cylindrical structure. There is a ligand-gated ion

channel in the center. (Roy-Byrne 2005) (OLSEN,

Tobin 1990) (Bruce 2021). It allows chloride ions to

move in and move out, using this mechanism, it can

regulate excitability. And there are many agonists and

antagonists to accommodate the process of GABA

binding with GABAA receptor, which plays role in

curing anxiety disorders, like benzodiazepines.

3.1 The Structure of GABAA Receptor

Electric organs of electric rays and eels, as well as

vertebrate skeletal muscle, contain GABAA

receptors. All are pentameric oligomers with a mass

of around 250 kilodaltons (kDa) and four different

types of subunits, each with a mass of about 50 kDa.

GABAA receptors in the central nervous system of

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

368

vertebrates appear to be made up of solely a, β and γ

polypeptides, with a total of four or five subunits. The

oligomeric subgroups differ in terms of

developmental stage, tissue type, and brain region, as

well as pharmacological qualities (OLSEN, Tobin

1990). As a result, the GABAA receptor is a

pentamer. It's also a heteropentamer, according to a

number of studies. There are several molecular

families of subunits that have been found, including

those α with 6 isoforms, β with 3 isoforms, γ with 3

isoforms, θ with 1 isoform, and ρ with 3 isoforms

(Tallman 2002). Furthermore, when viewed from the

extracellular space, the receptor complex is known to

consist of 2 α subunits alternating with 2 β subunits

ordered b-a-b-g-a in a clockwise orientation and a

single γ subunit (Sherif 1995) (Duffy 2004) (Liu

2007) (Zafar 2018). The tri-heteromeric receptor,

which consists of two α, two β, and one γ subunit, in

the vertebrate brain, is the most common subunit

combination, despite the fact that there are multiple

possible layouts (Chang 1996) (Farrar 1999) (Tretter

1997).

3.2 Ligand-gated Channel

There are two GABA binding sites in each receptor

complex, but only one benzodiazepine binding site.

The GABA binding sites are found at the junction of

the two β subunit pairs that alternate, while the lone

benzodiazepine binding site is found at the crossroads

of the single α and γ subunit pairings (Roy-Byrne

2005). There are many different subtypes to choose

from due to the numerous diverse subunits and their

arrangements, each with its own affinity for GABA,

chloride channel kinetics, and affinity for different

benzodiazepine ligands (Roy-Byrne 2005). The vast

majority of these receptor complexes, according to

evidence, are made up of α1 subunit in combination

with β2 and γ2 subunits (Mohler HF 2001). The α2 or

α3 receptor subtype is likely to be responsible for

benzodiazepine sedation (Rudolph U 1999) (Lydiard

2003).

3.3 GABAA Receptor Channel

There are GABAA receptors play a critical role in

balancing excitatory transmission. When activated by

GABA, the protein subunits undergo conformational

changes, resulting in the brief development of a

channel along the cylinder's axis via which chloride

ions can flow from the outside to the interior (Kalueff

2007). The chloride ions flowing into the cytoplasm

will cause hyperpolarization, so GABA is considered

an inhibitory neurotransmitter. As a result, GABA is

known to counteract the excitatory neurotransmitter

glutamate's effect (Tillakaratne 1995).

3.4 Pharmacology

The GABA-benzodiazepine receptor, also known as

the GABAA receptor or the benzodiazepine receptor,

may play a role in the pathophysiology of anxiety as

well as its treatment (Figure 2). GABAA receptors

are important since they are where benzodiazepines

act. It refers to a complex glycoprotein that has

binding sites for a variety of benzodiazepine drugs

with potent anxiolytic properties (Roy-Byrne 2005).

The reason why benzodiazepine can be used to treat

anxiety disorder on GABAA receptor is that

benzodiazepines allosterically modulated GABAA

receptors, which are used for their sedative,

anxiolytic, anticonvulsant, and muscle relaxant

actions (Rudolph 2018). To be specific, the

neurotransmitter GABA opens the chloride channel

when it binds to GABAA receptor while

benzodiazepines control this opening (Sigel 2018).

Furthermore, benzodiazepines influence this channel

opening triggered by either agonist binding site (Baur

2005).

Figure 2: The Structure of GABAA receptor.

Benzodiazepines are effective as a drug to treat

anxiety disorder when they bind with GABAA

receptors containing specific subunits. The most

sophisticated drugs, which target GABAA receptors

with α2 and α3 (positive allosteric modulation) and

α5 subunits (negative allosteric modulation), are now

being evaluated in clinical trials for anxiolytic effects,

and using one subunit (negative allosteric

modulation) to avoid functional effects at GABAA

receptors, while using only α1 subunit to avoid

functional effects at GABAA receptors (Rudolph

2018). In addition to their anxiolytic effect, which is

Targeting GABA to Cure Anxiety Disorder in Various Methods

369

mediated by α2 and potentially also by α3-containing

GABAA receptors, benzodiazepines exhibit sedative

properties mediated by α1-containing GABAA

receptors (Rudolph, 2018). Benzodiazepines are only

sensitive to receptor assemblies that have an a1

subunit next to g2 (Minier 2004). As a result, when,

benzodiazepines combine with different sub-type of

GABAA receptors, they have sedative, hypnotic,

muscle relaxant, and anticonvulsant properties, with

extremely minimal risk of overdosing (Sigel 2018).

4 GABAB RECEPTOR

The GABAB receptor, which is a G-protein-coupled

receptor, suppresses adenylate cyclase activity and

mediates synaptic inhibition's gradual and sustained

component (Bowery N 2004). GABAB receptors,

highly expressing in the limbic systemare, were

found in almost all neuronal cells, especially GABAB

(1) receptor. GABAB (1) and GABAB (2) are two

subunits of the GABAB receptor that heterodimerize

to create the functional GABAB receptor. The

orthosteric ligand binding site is found in the

GABAB (1) subunit, whereas the GABAB (2)

subunit, responsible for G-protein activation,

contains positive allosteric modulator binding sites

(Gassmann M 2012).

4.1 Baclofen

Baclofen was a powerful and selective agonist of

GABAB receptor in 1980, and it was shown that

baclofen inhibited neurotransmitter release in the

central nervous system when it acted on it. GABAB

receptor agonists, including baclofen, have a lot of

preclinical evidence that they could be useful in the

treatment of anxiety disorders (Felice D 2016)

(Vinkers CH 2010). Baclofen, the first known GABA

derivative, was created in 1962 by combining a

halogenated phenylring with carbon to create a

molecule that could cross the blood-brain barrier

(BBB). The functions of baclofen are mainly used as

a muscle relaxant and antispastic. Research of

baclofen revealed a number of drawbacks: it couldn't

passively penetrate the BBB and had a short duration

of action and rapid tolerance development in the

patient (Felice 2020).

Efforts have been made to obtain baclofen

analogs, but no superior drug options have emerged.

One of these compounds was phenibut, which was

made by merely removing the chlorine atom from

baclofen. The molecule has anxiolytic and nootropic

properties, however it was quickly determined that it

was not GABAB receptor-selective. Other

experiments attempted but failed, to rigidify the

baclofen structure by inserting groups like ethylene

and propylene. Some efforts to obtain baclofen

analogs resulted in clinically authorized medications,

such as pregabalin, vigabatrin, and gabapentin,

although these were discovered to act through distinct

processes and bind receptors other than the GABAB

receptor. Although some inconsistent outcomes have

been reported, baclofen treatment has been

demonstrated to attenuate anxiety-like behavior in

numerous rat models and mouse models. For

example, one study found that baclofen was useful in

the Vogel conflict test, whereas another found that it

had no impact (Lu Y 2016). The side effects of

Baclofen included muscular relaxation，sedation，

vertigo ， somnolence, and hypothermia (Agabio

2013). PAMs, one of GABAB receptors, have a lower

risk of receptor desensitization/tolerance as compared

to baclofen， which was typical GABAB receptor

agonists.

Table 1: The typical medicine, target receptor, mechanism

and side-effects.

Name of

Medicine

Target

receptor/Mechanism

Side-effect(s)

Reboxetine Increased GAD65

expression

Dry mouth,

Constipation.

Vigabatrin GABA-T inhibitor,

raise brain

GABA levels by

irreversibly blocking

GABA-T

Problems walking or

feeling uncoordinated,

feeling dizzy, shaking,

joint pain.

Phenylethyli

denehydrazin

e (PEH）

Inhibit GABA-T No clinical trials, thus

no known side-effect.

Tiagabine

hydrochlorid

Selective GABA-

reuptake inhibitor,

increases GABA tone

via GAT1 blockade

Inability to concentrate,

dizziness, drowsiness,

nervousness, irritability.

Antagonists

cholecystoki

nin

Blocks the receptor

sites for the peptide

hormone

cholecystokinin

(CCK), a

neuropeptide that

modulates the

GABAergic system

Nausea, vomiting,

constipation,

drowsiness.

Benzodiazepi

GABAA Dependence, rebound

anxiety, memory

impairment, and

discontinuation

syndrome.

Baclofen GABAB Short duration of action

and rapid tolerance

development.

Positive

Allosteric

modulators

(PAMs)

GABAB Addiction liability and

respiratory depression.

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

370

4.2 Positive Allosteric Modulators

(PAMs)

Compared with receptor agonists such as baclofen,

PAMs have several advantages: (1) PAM binding

causes receptor potentiation rather than direct

activation; (2) When the allosteric binding site is

saturated, the target receptor will not be down-

regulated or over-stimulated (Gjoni T 2008) (Gjoni

2009). GABAB receptor agonists, such as PAMs,

will produce anxiolytic-like effects, whereas

defunction of GABAB receptor (in GABAB (1) and

GABAB (2) animals models) will produces

anxiogenic-like effects. Losing the function of either

the GABAB (1a, 2) or GABAB (1b, 2) receptor

subunit isoform alone, however, exhibited no effect

on anxiety-like behavior in these mice, most likely

because they still retained functioning GABAB

receptors (GABAB(1b,2) or GABAB(1a,2),

respectively). GABAB receptor antagonists have an

unknown effect on anxiety, however they appear to

be anxiolytic in some situations, similar to

agonists/PAMs. The exact mechanism of the

anxiolytic effects of GABAB receptor antagonists

and agonists/PAMS, which should have opposing

pharmacological actions, are still unknown. This

could be because GABAB receptors are located both

pre- and post-synaptically, and medicines' efficacy

and timings may differ (Freyd T 2017). Despite this,

data suggested that the GABAB receptor could be a

promising therapeutic target for anxiety disorders.

Moreover, the typical treatments for anxiety disorders

are as long as their respective characteristics, as

shown in Table 1.

5 CONCLUSIONS

There are various methods of anxiety treatment by

using GABA. Includes modulate GABA metabolism,

regulating GABAA and GABAB receptor. There are

several ways of GABA regulations such as GAD,

which could increase the expression of GABA-

related gene and increase the amount of GABA, then

the number of receptor increases which cause anxiety

to be inhibited. The second way is to use a GABA

transporter, which could inhibit the metabolism of

GABA, then the number of GABA increases, and

result in the rise of GABA level. GAT also plays an

important role, which regulates the duration and

intensity of GABAergic activity presynaptically and

postsynaptically. These are the method that

introduced in modulating GABA metabolism.

GABAA is crucial, and the main therapeutic target in

anxiety disorder. Benzodiazepine is an essential part

of anxiety. It reacts and combines with specific

subunits in the GABAA receptor which ultimately

reduces anxiety. GABAB is also a significant but less

developed receptor to cure anxiety. Baclofen which is

a GABAB agonist and PAM increases the effect of

enzymes which could ultimately decrease the level of

anxiety. However, recent studies and research shows

there is a sea of side effects and obstacles during

therapy. As benzodiazepine can cause sleep and

baclofen had a short duration of action and rapid

tolerance development. Fixing these problems is the

real question that is facing and hope to fix in the

future.

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