The GABA system - target of a wide range of
drugs active on the CNS-
• Anxiolytics ,
• General anesthetics, and
• In 19th century – was known as a metabolite of plant
• In early 20th century - was isolated as an amino acid
in the brain of mouse through paper
• In 1950 Robert and Frankel discovered GABA in
THREE MAJOR TYPES
I. GABA A
GABA A GABA B
Type Ionotropic Metabotropic
Location Widely spread ,mainly GABA
Subcellular event Postsynaptic inhibition by ↑
Presynaptic inhibition by ↓
Postsynaptic inhibition by
Channel blocker Picrotoxin NA
GABA A RECEPTORS
• Ligand gated ion channel
• Distributed throughout the brain.
• It is a heteropentamer, made of five subunits .
• Ligand binds at the interface between α and β
domain ( 2 α,2 β,1 γ)
• Different types of GABA A receptors present-
depending on the type of subunit .
• Subunits – alpha(1-6), beta(1-3), gamma(1-3), delta,
epsilon, pi, theta and rho.
• Different types of GABA A receptors - present in
different regions of the brain , at different levels of
GABA A receptor when activated, an increase in the
Increase in the influx of Cl- ions causing membrane
Increase in the threshold for generating action potential.
• Allosteric modulation
The site where modulators bind is different from the
site of binding of GABA agonist – known as
“allosteric” site . Modulator - “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. E.g. Bicuculline.
• G-protein coupled receptor.
• Dimer of two, seven transmembrane spanning subunits
held together by a coil – coil interaction btw their C-
• Activation of receptors occurs when GABA binds to the
extracellular domain of the B1 subunit which produce an
allosteric change in the B2 subunit which couples to the G-
• Widely distributed throughout the CNS.
GABA B RECEPTORS
• Located both pre- and post-synaptically.
• Presynaptically- auto-receptor. Inhibits voltage gated
calcium channels,thus decrease neurotransmitter
• Postsynaptically – inhibitory – long lasting
hyperpolarization by activating K+ channel.
• Transmitter gated chloride channel
• Retina,spinal cord,superior colliculus,pituitary
• Physiological role is not yet discovered.
GABA C RECEPTORS
DRUGS ACTING ON GABA A RECEPTORS
GABA Endogenous agonist→promotes chloride influx
Muscimol Agonist at GABA A site
Bicuculline competitive anta
gonist at GABA A binding site
Picrotoxin Blocks chloride channel noncompetitively;acts on picrotoxin sensitive
Barbiturate Agonist at allosteric site,prolong GABA action,open chloride channel
Open chloride channel directly,Allosteric facilitation of GABA
Benzodiazepine Agonist at allosteric BZD site→facilitate GABA action
β -carboline Inverse agonist at BZD site→impede GABA action
Flumazenil Competitive antagonist at BZD site
• Powerful sedative,anxiolytic & anticonvulsant
• Selective potentiation of GABA effect on
GABA A receptors.
• Binds to accessory site on GABA A receptor →
facilitation of GABA binding
• Binding of BZD → increases frequency of
chloride channel opening -GABA facilitatory
• Binds to barbiturate binding site on GABA A
• increase the lifetime of chloride channel opening
induced by GABA → potentiate GABA ergic
inhibition - GABA facilitatory action
• At high conc. Barbiturates directly increase chloride
conductance- GABA mimetic action
• Enhance BZD binding to their receptors
DRUGS ACTING ON GABA B RECEPTORS
Baclofen Selective agonist
2-Hydroxy-saclofen Competitive antagonist
γ-Hydroxybutyrate weak agonist