GABA SYSTEMS IN

PSYCHIATRY
Chairperson: Dr. Kavitha, Asst. Prof MD Psychiatry
Presenter: Dr. Sheeba, PG MD Psychiatry.
 Objectives
• Introduction
• Synthesis
• Transporters
• Receptors
• Clinical aspects
• Summary
GABA (γ-Aminobutyric Acid)
• GABA is the principle inhibitory neurotransmitter in
the brain

• regulatory role in reducing the activity of many

neurons.

• GABA is produced OR synthesized, from the amino

acid glutamate

• GABA differs from glutamic acid, only by the removal

of a single carboxyl group
• Within the CNS GABA is synthesized in
GABAergic neurons. These are usually small
inter neurons with short axons.
• Projection neurons, such as the Purkinje cells
in the cerebellum and the striato-nigral and
pallido-nigral neurons in the basal ganglia are
GABAergic.
• Once formed in the pre-synaptic neurons ,
GABA is transported by VIAATs into synaptic
vesicles

• GABA’s synaptic action s are terminated by the

pre-synaptic GABA transporters or by the
enzyme GABA transaminase.
SYNTHESIS
GABA metabolism & uptake
 TRANSPORTERS
• Two major subclasses of plasma membrane
transporters which are presynaptic, and others are on
glial membranes.

• First subclass :sodium/chloride-coupled transporters,

called the solute carrier SLC6 gene family-GABA.

• Second subclass :comprised of high-affinity glutamate

transporters, called the solute carrier SLC1 gene family.
• Three subclasses of intracellular synaptic vesicle transporters for
neurotransmitters:

• SLC18 gene family :1. vesicular monoamine transporters

(VMATs) for serotonin, norepinephrine, dopamine, and
histamine .
2. vesicular acetylcholine transporter
(VAChT);
• SLC32 gene family :vesicular inhibitory amino acid transporters
(VIAATs);
• SLC17 gene family :vesicular glutamate transporters [vGluT1–3 ].
 RECEPTORS
• GABA A

• GABA B

• GABA C
 GABA receptors
GABA-A receptors are Iono-tropic and mostly
postsynaptic receptors, located at the apical
dendrite of the neurons

• Composed of five subunits ,each subunit has

Four Trans-mebrane regions.

• Depending upon which subunits are present ,

functions can vary significantly
GABA A RECEPTOR
• GABA acts post-synaptically with GABA-A
receptors - allows the chloride (Cl) ion channel
opening increasing the conductance of Cl-
• GABA-A receptors activation -
hyperpolarization of the neuronal membrane -
reduces cell excitability - inhibitory actions of
GABA
 BZD SENSITIVE GABA-A RECEPTOR
• BZD bind between α and γ subunit ,one BZD per
receptor complex.

• Post synaptic in location and mediate phasic type

of inhibition.

• BZD acting on α 2/3 subunit exert an anxiolytic

effect,α1 subunit is important for regulating
sleep
 BZD INSENSITIVE GABA A RECEPTOR

• Located extrasynaptically .mediate tonic type

of inhibition.
• Bind to other modulators like naturally
occuring neurosteroids,alcohol,general
anesthetics.
• Binding site between α and δ subunit
 GABA B RECEPTOR
• GABAB receptors are a member of the
Superfamily of G-protein-coupled receptors
expressed in the cell membrane.
• These receptors generally exert an inhibitory
effect on neuronal excitability by generating
hyperpolarizing potentials that are much
slower in onset and longer in duration than
those mediated by GABAA receptors.
 GABA receptors
• GABA-B receptors were initially shown to be
autoreceptors - regulating GABA
neurotransmissions
• GABA B receptors are often located on
presynaptic terminals where they serve to
inhibit transmitter release by reducing the
efficacy of action potentials to activate Ca 2+
influx.
• postsynaptic neurones – activation - an
increase in membrane K+ conductance -
neuronal hyperpolarization
 NEUROPSYCHIATRIC ASPECTS
• HUNTINGTON DISEASE
• ANXIETY AND DEPRESSION
• SCHIZOPHRENIA
• ANGELMAN SYNDROME
• ALCOHOLISM
• ALZHEIMERS
• STIFF PERSON SYNDROME
• DRUGS
 HUNTINGTONS DISEASE
• A marked reduction in the enzyme responsible
for the synthesis of GABA (glutamic acid
decarboxylase, GAD) in the putamen and globus
pallidus was demonstrated
• Reduced levels of GABA in the basal ganglia and
substantia nigra leads to the movement disorder.
• GABA receptors are depleted in the striatum
early in the disease, and before there is extensive
cell loss and atrophy.
 Anxiety and depression
• GABAergic dysfunction associated with panic disorder &
major depressive disorder.
• chronic stress can reduce and eventually can deplete
GABA levels, antidepressants upregulate GABA receptors
• Upregulation of the GABA A receptor α1 and β3 subunits
in the cerebral cortices of depressed patients who
committed suicide.
• The reduced levels of GABA in the occipital cortex in
episodes of major depressive disorder normalized with
effective treatment with SSRI or with ECT.
 SCHIZOPHRENIA
• Loss of GABAergic neurons in the
hippocampus results in a disinhibition of the
glutamatergic pyramidal output which also
results in elevated subcortical dopamine
release and psychosis.
• This degradation of the inhibitory feedback
could account for the cognitive deficits and
negative symptoms.
• Two proposed mechanism:
• Through NMDA receptors on GABAergic
inhibitory interneurons
• Defect in the GABAergic system of the frontal
cortex in schizophrenia - limited to the
parvalbumin-class of GABAergic interneurons
• associated with both decreased numbers and
abnormalities in the distribution of GABAergic
neurons in the cortex
• decrease in the number of GABA containing
inter neurons
• decreased GAD activity has been found in the
nucleus accumbens, putamen, amygdala and
the hippocampus
 Angelman syndrome
• Due to Deletion in 15q12 of maternal origin
[dominant].
• Frequent deletion of GABA B-3receptor subunit.
• Presents with 1.Developmental delay,
2. Seizures
3. Frequent laughter
4. Ataxia [poor control of voluntary
muscle movements]
 ALCOHOLISM
• Intoxication has a dual action of enhancing GABAergic receptor
function and attenuating the NMDA receptor function.
• Most potent effects especially on the GABA-A receptor (GABA A),
contributing to the sedating, sleep-inducing, anticonvulsant, and
muscle-relaxing properties of alcohol.
• Persistent abuse and dependency on ethanol result in a
downregulation of GABA A receptors and an upregulation of
NMDA receptors
• acute discontinuation of ethanol results in a hyperexcitable state
characterized by delirium tremens.
 STIFF PERSON SYNDROME
• Autoimmune condition

• patients have autoantibodies to glutamic acid

decarboxylase(GAD).

• Characterized as having progressive and fluctuating muscle

rigidity with painful spasms.

• Presents with anxiety, mediated by changes in the GABAergic

system.

• Treatment include diazepam or clonazepam.

 GABA AND INSOMNIA
• Two neurotranmitters regulating the
sleep/wake switch is histamine from TMN and
GABA from the VLPO
• When the sleep/wake switch is on ,wake
promoter TMN is active and histamine is
released
• When sleep promoter VLPO is triggered the
sleep/wake switch is turned off and GABA is
released in the TMN to inhibit wakefulness
 γ-Hydroxybutyrate (GHB), liquid ecstasy OR
XYREM
• GHB shows initial euphoria and reduced
anxiety, with higher doses.
• mechanism of action is to promote GABAergic
neurotransmission causes sedation .
• approved for the treatment of narcolepsy and
improves slow-wave sleep.
 GABA AGONISTS

1. PROPOFOL: GABAA • NON BZD:

agonist. ZALEPLON
It induces the presynaptic ZOLPIDEM
release of GABA
ESZOPICLONE
2. ETOMIDATE:acts at the
β2 and β3 subunits of the
GABAA receptor.
THESE ARE ANESTHETIC
AGENTS.
 BENZODIAZEPINES
• Benzodiazepines appear to bind to the region of
the receptor between the γ2/γ3 subunit and the
α1/α2/α3 subunit of GABA A receptor .
• BZD’s enhance opening of inhibitory chloride
channels the action is called “positive allosteric
modulation,”
• reduces anxiety ,induce sleep, block convulsions,
block short term memory, relaxes muscles.
Anticonvulsants
 GABA A Allosteric Modulators
Brexanolone, [Allopregnanolone]
• Treatment of postpartum
depression[Approved in 2019].
• Neurosteroid which positively modulates the
GABAA receptor.
• Negative allosteric modulator of the nicotinic
acetylcholine receptor and may have action on
serotonin HT3 as well.
 SUMMARY
• GABA is inhibitory neurotransmitter.
• produced from glutamate by GAD Enzyme.
• Transporter is VIAAT.
• Receptors: GABA A, B ,C.
• These receptors act through tonic and phasic
inhibition.
• GABA A,C are ligand gated.
• GABA B is GPCR mediated.
 NEUROPSYCHIATRIC ASPECTS
• HUNTIGTON DISEASE: DECREASED GABA in basal ganglia and
substantia nigra.
• ANXIETY AND DEPRESSION: GABAnergic dysfunction.
• SCHIZOPHRENIA: Loss of GABAnergic neurons; glutamate
INCREASED
• ANGELMAN SYNDROME: Del of GABA- B 3 receptor subunit
• ALCOHOLISM: Dependency : downregulation of GABAA
receptors and an upregulation of NMDA receptors
• STIFF PERSON SYNDROME: autoimmune condition with
autoantibodies to GAD enzyme which help in GABA Synthesis.
• DRUGS: Memantine , Topiramate , Acamprosate , Baclofen,
Antiepileptics , GHB, BZD’S.
 REFERENCES:
1. Studyguide for Stahl’s Essential Psychopharmacology: Neuroscientific
Basis and Practical Applications by Stahl, Stephen M., ISBN
9781107686465. Cram101; 2017.31-39,53-55,65,101-109,255-263,

2. David D, Fleminger S, Kopelman M, Lovestone S, Mellers J. Lishman’s

organic psychiatry: A textbook of neuropsychiatry. 4th ed. Hoboken,
NJ: Wiley-Blackwell; 2012.

3. Sadock BJ, Sadock VA, Ruiz P. Kaplan and sadock’s comprehensive

textbook of psychiatry. 10th ed. Baltimore, MD: Wolters Kluwer
Health; 2017.