Gamma Amino Butyric Acid (GABA) is the major
inhibitory neurotransmitter of the mammalian CNS.
It is broadly distributed in the brain.
GABA acts at inhibitory synapse in the brain by binding to
specific transmembrane receptor in the plasma
membrane of both pre and postsynaptic neuronal
Implicated in broad range of neuropsychiatric
disorders like seizures, anxiety disorders,
schizophrenia, alcohol dependence etc.
GABAergic neurons directly project to the substantia
nigra pars reticulata
Striatal GABergic neurons also project to the globus
pallidus to synapse on the pallidal-subthalamic
GABAergic neurons that regulate the excitatory
output from the subthalamic nucleus.
In cerebellum, GABAergic Purkinje cells are its main
Synthesis and Storage
Synthesised from amino acid L- Glutamic acid by the
Glutamic acid Decarboxylase (GAD) an enzyme
present in neurons and peripherally in pancreatic islet
cells and body fluids.
It catalysis the removal of α- carboxyl group.
It is most highly concentrated in the substantia nigra &
globus pallidus nuclei of the basal ganglia, followed by
GABA transporter (GAT)
GAT 1 is identified as a presynaptic receptor.
While GAT 2-4 receptor location have yet to be
Tiagabine blocks GAT1 receptor – increase in
synaptic GABA concentration – anticonvulsant
GABA is catabolised by GABA transaminase
GABA-T is a cell surface, membrane bound enzyme
expressed by neurons and glia, oriented towards
Inhibited by valproic acid and vigabatrin (use in
Relieving premenstrual syndrome (PMS).
Regulating the release of sex hormones.
Treating attention deficit-hyperactivity disorder (ADHD).
Promoting lean muscle growth.
Stabilizing blood pressure.
lower elevated blood sugar levels in diabetics.
Ligand gated ion channel.
Distributed throughout the brain.
It is a heteropentamer, made of five subunits with
each subunit containing four α helical membrane
Ligand binds at the interface between α and β
There are many different types of GABA A
receptors depending on the type of subunit
Subunits also called isoforms – alpha(1-6),
beta(1-3), gamma(1-3), delta, epsilon, pi, theta
Different types of GABA A receptors are present
in different regions of the brain and at different
levels of development.
The site where modulators bind is different from
the site of binding of GABA agonist – known as
“allosteric” site and the modulator is called
“allosteric modulator”. The modulator has no
activity of its own.
Positive Allosteric Modulation: ligand binds
allosteric site and enhance the action of
Negative Allosteric Modulation: ligand binds to
the allosteric site while an agonist is also bound
and the channel opens less frequently then when
GABA A receptors with alpha 4/6 and delta
subunit are insensitive to benzodiazepines.
Binds to modulators – naturally occurring
neurosteroids, alcohol and some general
Located extrasynaptically. Regulated by
extracelullar GABA molecule that has escaped
reuptake and enzymatic destruction
Mediate tonic inhibition of postsynaptic neuron
Not sensitive to BZD – no anxiolytic actions of
GABA A receptor when activated, mediates an
increase in the conductance.
Increase in the influx of Cl- ions causing
Increase in the threshold for generating action
GABA A receptor with alpha 1/2/3, beta, gamma 2/3.
Postsynaptic in location – phasic inhibition. Bursts of
inhibition triggered by peak concentration of
synaptically released GABA.
Sensitive to BZD – Anxiolytic actions.
Alpha 1 – most important for regulating sleep –
target for various sedative hypnotic agents.
Alpha 2/3 most important for regulating anxiety.
Abnormal expression of alpha 2, gamma 2 or delta
Differentiated from GABA A by
Insensitive to GABA A antagonist Bicuculline.
Activated by Baclofen
Member of G-protein couples receptor. Dimer of two
seven transmembrane spanning subunits.
Located both pre and post-synaptically.
Presynaptically- Activation of presynaptic GABA-B
receptors decreases the release of GABA and of
Postsynaptically – Activation of postsynaptic GABA-
B receptors modulates the opening of potassium
channels, which induces an intracellular potassium
I. Anxiety disorders
Amygdala central circuit – amygdala plays
central role in the expression of fear and anxiety.
Cortico-Striatal-Thalamo-Cortical (CSTC) loop –
linked to worry and obsessions across the
spectrum of anxiety disorders.
GABA is the principal inhibitory neurotransmitter
in the brain and serves an important regulatory
role in in reducing the activity of many neurons
including those in Amygdala and CSTC loop.
GABAergic dysfunction has been associated with
anxiety disorders, esp with panic disorder.
Magnetic Resonant Spectroscopy reveals
significant reduction in GABA levels in the Basal
II. Mood disorders
Magnetic Resonant Spectroscopy reveals
significant reduction in both GABA and
Glutamate in Prefrontal cortex in Major
Post mortem studies revealed up regulation of
the GABA receptors alpha1 and 2 subunits,
consistent with a reduction in GABAergic
Reduced levels of GABA in occipital cortex in
episodes of major depressive disorder
normalised with effective treatment with SSRIs
In animal studies – valproate, carbamazapine,
lithium and lamotrigine a/w in increase in GABA
turnover in brain.
Endocrinal hypothesis: estrogen induces
downregulation of GAD resulting in inhibitory
action on GABA formation resulting in increased
activity of pyramidal cells.
Corticobrainstem glutamate pathways and
NMDA receptor function hypothesis
Descending glutaminergic pathway projects from
cortical pyramidal cells to brainstem
neurotransmitter centres inclusing raphe for
serotonin, VTA and substantia nigra for
dopamine and locus ceruleus for norepinephrine.
Corticostriatal glutamate pathway (CSTC loop)
Descending glutaminergic output from the
pyramidal cells in cortex nucleus
accumbens in ventral striatum forming first
leg of the CSTC loop.
Ascending pathway from thalamus to cortex –
return leg of the CSTC loop.
GABA neurons located in the thalamus acts as
the sensory filters and prevents too much
sensory input from penetrating the thalamus into
Dopamine inhibits GABA in CSTC loop
reduces the effectiveness of thalamic filter
opposes the excitatory input of the glutamate
from corticostriatal glutamate projections.
In epilepsy, abnormal electrical discharges are
due to hyperexcitable neurons with sustained
Decreased GABA inhibition of cortical excitability
is one of the proposed mechanism.
Penicillin induced cortical injury causes seizures
through decreased GABA inhibition.
BZD and barbiturates reduces seizures by
enhancing GABA receptor current and valproate
through blockade of GABA catabolism.