AMINOACID NEUROTRANSIMITTERS, GLUTAMATE,GLYCINE, GABA

1. DR.V.L.NARASIMHA SEKHAR
1ST YEAR PG
DEPT OF PSYCHIATRY
SVRRGGH

2.  HISTORY
The father of modern neuroscience

3. After a presynaptic neuron is stimulated the delay is about 0.3 ms for
the postsynaptic neuron to respond. This is too long for electric
transmission.
If you stimulate the postsynaptic neuron , no response in the
presynaptic one. Polarization of communication between neurons.
Stimulation of presynaptic neuron may result in postsynaptic inhibition.
Difficult to explain in terms of direct passage of electrical event.
No relationship between the magnitude of the pre and postsynaptic
electrical event.

4.  Until the early 20th century, scientists assumed
that the majority of synaptic communication in the
brain was electrical.
 However, through the careful histological
examinations by Ramón y Cajal, a 20 to 40 nm
gap between neurons, known today as the
synaptic cleft, was discovered.
 The presence of such a gap suggested
communication via chemical messengers
traversing the synaptic cleft,

5.  In 1921 German pharmacologist Otto Loewi
confirmed that neurons can communicate by
releasing chemicals.
 Otto Loewi is credited with discovering
acetylcholine (ACh)—the first known
neurotransmitter.
 Some neurons do, however, communicate
via electrical synapses through the use of gap
junctions, which allow specific ions to pass
directly from one cell to another.

6.  DEFINITION OF NEUROTRANSIMITTER
 A chemical substance which is released at
the end of a nerve fibre by the arrivel of a nerve
impulse and , by diffusing across the synapse or
junction, effects the transfer of the impulse to
another nerve fibre ,a muscle fibre, or some other
structure.

7. 1. Presynaptic terminal should contain a store of the substance
(preferably in a sequestered form)
2. Applying the substance to a postsynaptic cell should mimic the
effects caused by stimulating the presynaptic terminal
3. If a drug is known to block a neurotransmitter, it should have the
same effect on this transmitter if it’s applied exogenously
4. A mechanism for the synthesis of this trasmitter must exist (including
the appropriate precursors/enzymes in the terminal)
5. A mechanism for inactivation of the transmitter must exist (catabolic
enzymes for its degradation/ reuptake system, etc)

9. 9
Table 1. Classes of CNS Transmitters
Neurotransmitter % of
Synapses
Brain
Concentration
Function Primary
Receptor Class
Monoamines
Catecholamines : DA, NE,
EPI
Indoleamines: serotonin
(5-HT)
2-5 nmol/mg
protein
(low)
Slow change in
excitability (secs)
GPCRs
Acetylcholine (ACh) 5-10 nmol/mg
protein
(low)
Slow change in
excitability (secs)
GPCRs
Amino acids
Inhibitory: GABA,
glycine
Excitatory: Glutamate,
aspartate
15-20
75-80
μmol/mg
protein
(high)
μmol/mg
protein
(high)
Rapid inhibition
(msecs)
Rapid excitation
(msecs)
Ion channels
Ion channels

12.  (1) a high concentration within presynaptic terminals (especially
within synaptic vesicles),
 (2) release from the pre synaptic terminal during membrane
depolarization,
 (3) the presence of specific receptors in the postsynaptic
membrane,
 (4) an inactivation mechanism (removal of molecules from the
synaptic cleft).
 Three amino acids (glutamate, GABA, and glycine) meet all of these
criteria.

14.  Acidic non essential amino acid.
 Important as the building block of protein
synthesis.
 As a neurotransmitter in CNS.
 Called king of neurotransmitters
 Also called master switch of brain.
 Major excitatory neurotransmitter
 Concentrated in the order of 10mM in brain which
is highest of any NT.
 Present in 80% of brain synapses esp. the
dendritic spines.

15.  The repolarization of neuronal membranes that have been depolorized
by glutamatergic neurotransmission may account for as much as 80
percent of the energy expenditure in the brain.
 The concentration of glutamate in brain is 10 mM, the highest of all
amino acids, of which approximately 20 percent represents the
neurotransmitter pool of glutamate.
 The postsynaptic effects of glutamate are mediated by two families of
receptors. The first are the glutamate-gated cation channels that are
responsible for fast neurotransmission.
 The second type of glutamate receptor is the metabotropic glutamate
receptor (mGluR), which are G-protein-coupled receptors like α
adrenergic receptors and dopamine receptors. The mGluRs primarily
modulate glutamatergic neurotransmission.

16.  Glutamate is excluded from BBB and is
synthesized denovo from
1. Glucose via krebs cycle
2. Glutamate recycling called glutamine cycle.
3. Aspartate
4. α- oxo glutarate
 Of these 40% of glutamate for
neurotransmission is obtained via
recycling by glutamine cycle.
 20% from glucose through kreb’s cycle.

17. Glutamate fast neurotransmission
Synthesis, packaging, reuptake, degradation
(error -
should be
EAAT)

18.  Glutamate is transported across membranes of
synapse by Na+2 dependent transporters called
EAATs.
 5 types
 EAAT1 - astrocyte
 EAAT2 – astrocytes, forebrain –implicated in ALS.
 EAAT3 – upper motor neurons
 EAAT4 – cerebellar purkinjee cells
 EAAT5 – retina
 Of these EAAT1 & 2 are involved in the reuptake
and release of glutamate during glutamine cycle.

19.  VGLUTs are expressed in presynaptic neuron for
transport of glutamate into vesicles once it is
synthesized
 These are 3 types:
1. VGLUT1 - cortex
2. VGLUT2 – diencephalon, brainstem
3. VGLUT3 – co-transmitter in non glutamatergic neurons.

21.  Glutamate is involved as a NT in the
following pathways:
 All primary sensory afferent systems
 Thalamocortical projections
 Pyramidal neurons of corticolimbic
regions
 Temporal lobe circuit of 4 synapses
involved in new memory formation
 Climbing fibres of cerebellar cortex
 Corticospinal tracts

22.  All primary sensory afferent systems appear to use glutamate
as their neurotransmitter including retinal ganglion cells,
cochlear cells, trigeminal nerve, and spinal afferents.
 The thalamocortical projections that distribute afferent
information broadly to the cortex are glutamatergic.
 The pyramidal neurons of the corticolimbic regions, the major
source of intrinsic, associational, and efferent excitatory
projections from the cortex are glutamatergic.
 A temporal lobe circuit that figures importantly in the
development of new memories is a series of four glutamatergic
synapses:
 The perforant path innervates the hippocampal granule cells
that innervate CA3 pyramidal cells that innervate CA1
pyramidal cells.
 The climbing fibers innervating the cerebellar cortex are
glutamatergic as well as the corticospinal tracks.

23.  Glutamate receptors are present in synaptic and
nonsynaptic regions of neuronal membranes throughout
the CNS.
 Some glutamate receptors are also found in the
membrane of astrocytes and oligodendrocytes.
 two general classes of glutamate receptors.
1. Ionotropic glutamate receptors (iGluR).
1.α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA)receptors
2.kainic acid (KA)receptors
3.N-methyl-D-aspartic acid (NMDA) receptors
1. metabotropic receptors (mGluR)

26. TYPES OF GLUTAMATE RECEPTORS
Ionotropic receptors Metabotropic

27.  N – methyl – D – aspartic acid receptor.
 Tetrameric cation conductance channel
 3 main subunits which are further subdivided by
splicing
 NR1, NR2(A, B, C, D), NR3(A, B)
 NR1 has the glycine/ d-serine binding site which
is the ion channel
 NR2 has the glutamate binding site
 NR2 further divided into 4 subtypes
◦ 2A – corticolimbic
◦ 2B – immature neurons
◦ 2C – cerebellum
◦ 2D - brainstem
 NR2B has highest ca+2 permeability

29.  NMDA receptors have a number of distinct recognition sites
for endogenous and exogenous ligands, each with discrete
binding domains.
 At present, there are at least seven pharmacologically
distinct sites through which compounds can alter the activity
of this receptor
 Drugs that affect NMDA receptor function are divided into
four groups: those acting at
1. the glutamate/NMDA recognition site, which is highly
conserved on the NR2 subunits;
2. the strychnine-insensitive glycine binding site
(presumably on the NR1 subunit), where glycine is
required as a coagonist for channel opening;
3. the intra-ion channel binding site, where Mg2+ sits
blocking ionic currents through the receptor at resting
potentials; and
4. modulatory sites such as the redox modulatory site, the
proton-sensitive site, the Zn2+ site, and the polyamine site.

30.  Conducts mainly Ca+2.
 Also called coincidence detector
 Activation requires simultaneous
occurrence of 3 events.
1. Depolarisation by AMPA receptor – removes
Mg+2 blockade
2. Binding of co-transmitter glycine / D –serine
3. Binding of 2 glutamate
4. Results in Ca+2 conductance
5. activates protein kinase
6. Leads to gene expression mainly c-fos

32.  The NMDA receptor has three characteristic features:
1. at resting potentials, it remains blocked by Mg2+.
Ionic currents through the receptor occur only if the
neuronal membrane is partially depolarized;
2. significant amounts of extracellular Ca2+ enter the
cell interior during activation of the receptor; and
3. the NMDA receptor–mediated neurotransmission
occurs slowly and lasts for a prolonged period.
Because of these properties, the NMDA receptor
serves a critical role in synapse development and
plasticity, including the phenomena of LTP and LTD.

33.  One of the most tightly regulated ion channel.
 Zn+2 and H+ inhibit NR2A
 Polyamine enhances channel opening in
NR2B
 Ca+2 influx reciprocally inhibits NR1 by
calmadulin
 Channel is sensitive to redox state.
 serine/threonine kinases, calcium/calmodulin-
dependent protein kinase II (CAMKII),
Ras/mitogen-activated protein kinase
(MAPK), and the Src family of tyrosine
kinases have been implicated in the
regulation of NMDA receptor functions

34.  α- amino 3– hydroxy 5– methyl 4- isoxazole
propionate (AMPA) receptors have broad distribution
 Predominantly post synaptic in location mediating
most EPSPs in CNS.
 Activated by binding of 2 glutamate moeties resulting
in Na+2 conductance causing depolarisation of post
synaptic membrane.
 Predominantly allows Na+ inside and K+ outside.
 Contain 4 sub units achieved by gene alternate
splicing GluR1-4.
 Subunits 1,3, 4 confer high permeability to Calcium
 Subunit 2 confers low permeability to calcium
 Regulated by phosphorylation based on activity.

35.  NMDA receptors mediate excitatory
neurotransmission in the CNS in different ways
from AMPA and KA receptors, although they are
often in close proximity in neuronal membranes
and are activated in tandem.
 AMPA receptor subunits exist in two different
forms, “flip” and “flop,” created by alternative
splicing.
 They are expressed predominantly in the “flip”
form in embryonic brains and gradually change
over to the “flop” form, which dominates in the
adult brain.

36.  In the second transmembrane domain, GluR1, 3
and 4 have a glutamine (Q) residue that results in
high Ca2+ conductance whereas GluR2 has an
arginine (R) in this position that severely restricts
Ca2+ passage and conducts only Na+,
 AMPA receptors require higher glutamate
concentrations for activation (10 to 100 µmol/L) than
the NMDA receptors.
 The AMPA receptor has at least three binding sites
at which agonists or antagonists can interact:
1. glutamate,
2. allosteric, and
3. intra-ion channel binding sites.

37.  Drugs of abuse increase expression of
GluR1 in VTA(ventral tegmental area) of
midbrain leading to sensitization.
 Chronic lithium and valproate are known to
decrease GluR1 in these regions
 Anti depressant, mood stabilizers like
lamotrigine and riluzole increase GluR1 and
GluR2 in hippocampal neurons

38.  KA is an effective agonist of AMPA receptors,
 it also activates its own distinct class of ionotropic receptors:
the KA-preferring receptors
 Five genes that encode the KA receptor (GluR5 through
GluR7 and KA1 and KA2).
 The five subunits are divided into two groups:
1. GluR5 through GluR7 represent the low-affinity kainate
binding site , whereas
2. KA1 and KA2 correspond to the high-affinity kainate binding
site.
 a common allelic variant of GluR7 (GRIK3) has been
associated with an increased risk for major depressive
disorder.
 GluR6 has genetic polymorphism on chr. 6q which are
associated with increased risk of mood disorders.

39.  They play a role in fast glutamatergic transmission in hippocampal
neurons.
 KA receptors have been shown to act presynaptically on mossy fiber
terminals on CA3 pyramidal neurons within the hippocampus.
 One unique feature of presynaptic KA receptors is that their activation
modulates transmitter release bidirectionally; weak activation enhances
glutamate release, whereas strong activation leads to inhibition (GluR6-
mediated).
 Involvement of presynaptic KA receptors in short-term plasticity at the
mossy fiber–CA3 synapse suggests that these facilitatory autoreceptors
may be important for the induction of LTP and LTD, as these forms of
long-term plasticity depend on Ca2+ accumulation within mossy fiber
terminals.
 Thus, bidirectional and activity-dependent regulation of transmitter
release by KA autoreceptors might have physiological significance in
information processing in the hippocampus and other CNS regions, as
well as its well-known pathological action contributing to epileptogenesis

40. Group Sub units Recepto
r
Second
messenger
Location
Group I 1, 5 Gq IP3/ DAG/
PLC
Post
synaptic
Group II 2, 3 Gi Inhibit
adenylyl
cyclase
Pre synaptic
Group III 4,6,7,8 Gi Inhibit
adenylyl
cyclase
Pre synaptic
The metabotropic receptor (mGluR) proteins belong to the
superfamily of GPCRs, all of which comprise seven-
transmembrane domains.
Divided into three groups according to the extent of amino acid
homology of their sequences, agonist sensitivity, and associated
signal-transduction mechanisms.

41.  Group I mGluRs are primarily localized postsynaptically at the periphery
of the postsynaptic density, where they can regulate currents through
iGluR channels.
 In contrast, group II and III mGluRs typically function as presynaptic
receptors involved in regulating the release of glutamate or other
neurotransmitters.
 The synaptic distribution and functional properties of mGluRs are
thought to be regulated by the interaction of various proteins with the C-
terminal domain of the mGluR
 Several of the mGluRs have been implicated in synaptic plasticity that
occurs in learning and memory.
 Knock-out of group I mGluRs has resulted in deficits in acquisition and
retention of spatial and motor learning.
 Similar studies in group II and III mGluRs exhibited no learning and
memory deficits; rather, deficits were related to visual processing and
increased epileptogenesis

42.  All three inhibit L type calcium channels and close potassium
channels
 I and II inhibit N type calcium channel as well
 Slow depolarisation , reduce excitability
 II and III inhibit release of glutamte and GABA
presynaptically by inhibiting P/Q calcium channel.
 Prevent excitotoxicity
 Implicated in schizophrenia.
 mGluR5 blocker restores degenerative changes of
azheimer’s in mouse models.

44. NMDA receptor activation in hippocampal CA1
pyramidal cell
Release of Ca+2
Activation of kinases/ phosphatases
CaMKII +NMDA receptor complex
Hyperphosphorylation
Integration of new AMPA receptors into post
synaptic membrane
Long term potentiation
New memory formation

45.  5 glutamte pathways relevant in schizophrenia:
1. Corticobrainstem
2. Corticostriatal
3. Thalamocortical
4. Corticothalamic
5. Corticocortical

46. Corticobrainstem pathway: a key regulator of
neurotransmitter release from cortex to brainstem NT
centres.
◦ Inhibits mesolimbic dopamine via GABA interneuron
in VTA.
◦ Excites mesocortical dopamine directly.
◦ Hypofunction results in mesolimbic dopamine
hyperactivity – positive symptoms and
◦ Mesocortical dopamine hypoactivity – cognitive,
negative and affective symptoms.

47.  Corticostriatal projections are part of CSTC(cortico-
striato-thalamo-cortical) loop involved in thalamic
sensory gating.
 Hypofunction of NMDA receptor in these pathways
results in failure of thalamic filter causing excessive
sensory information to reach cortex which leads to
positive symptoms.
 Thalamocortical projections are influenced by
mesolimbic dopamine neurons which become
hyperactive in NMDA hypofucntion.
 Corticothalamic pathways provide input to thalamus
and dysfunction causes dysregulation and failure of
filter.

48.  Corticocortical loops connect
DLPFC(dorsolateral prefrontal cortex),
VMPFC(DLPFC(ventrolateral prefrontal
cortex) and OFC(orbito frontal cortex) in three
different loops resulting in efficient information
processing in frontal cortex.
 Dysfuntion of NMDA receptor results in hypo/
over/ partial overactivation of these loops
leading to miscommunication and
schizophrenic symptoms.

50.  The neurodegenerative events in
schizophrenia may be because of
excitotoxicity.
 Chronic irreversible deterioration in
cognitive functions is hypothesized to be
because of excitotoxicity.

51. Excess NMDA receptor activation positive symptoms
Overactivation excess Ca+2
Excess enzyme activation free radicals
Dendrite destruction
Neuronal death negative, cognitive affective
symptoms

52.  Many susceptibility genes have been identified and
implicated in development of schizophrenia.
 A sufficient combination of genetic bias and
environmental stress leads to development of
schizophrenia.
 Many such genes have been identified.
 4 key genes associated with AMPA receptor, NMDA
receptor and abnormal synaptogenesis are
1. BDNF(brain-derived neuropathic factor) – a trophic factor
2. Dysbindin – formation of synaptic structures
3. Neuregulin - neuronal migration, myelination
4. DISC 1(Disrupted in scizophrenia)gene – neurogenesis,
migration and dendritic organisation.

53.  Abnormalities of these genes combined with excitotoxicity in fetal
brain leads to dysconnectivity in various brain regions resulting in
schizophrenia.
 In addition DAOA a gene for D – AA oxidase that removes D-
serine from synapse at NMDA receptor is also implicated.

54.  NMDA antagonists – decrease the excess
glutamate released to overcome NMDA
hypofunction
 Glycine agonists – glycine, D-serine, D-
cycloserine reduce negative, cognitive symptoms.
 GlyT1 inhibitors – sarcosine improves negative,
cognitive, depressive symptoms
 mGluR2/3 presynaptic agonists – decrease
glutamate release pre synaptically improve both
positive and negative symptoms. Also have 5HT2A
antagonism and neuroprotective action.
 Sigma agonists/ antagonists/ partial agonists
 Free radical scavengers.

55.  Glutamate excess and NMDA hyperactivation has
been implicated in bipolar depression.
 NMDA antagonists help in stabilising the mood
from below.
 Lamotrigine and riluzole decrease glutamate
release used in depression.
 Low single dose ketamine has rapid onset
antidepressant effect lasting for several days.
 Other NMDA antagonists like memantine and
amantadine are being tried.
 Novel agents:
◦ Compounds related to lamotrigine - JZP 4
◦ Drugs acting at sigma 1 site

56.  Excessive glutamate release from presynaptic
membranes leads to catastrophic activation of
NMDA receptors.
 Limited form is used in pruning the dendritic tree
 Excess results in excess entry of Na+ and Ca+2
along with water resulting in acute cell edema and
death.
 It also disrupts mitochondria, release of Cyt C and
apoptosis
 This has been implicated in
◦ Ischemic stroke
◦ Alzheimer’s disease, degenerative dementias
◦ Parkinson’s
◦ ALS

57. 57
Necrosis Apoptosis

58.  Activation of afferent C fibers with nociceptive stimuli
produces pain sensations that are enhanced during
pathological conditions.
 Activity-dependent increases in excitability are
induced in the spinal dorsal horn neurons by
repetitive stimulation of C fibers. This is thought to
contribute to the development and maintenance of
chronic pain symptoms.
 The NMDA antagonists, ketamine and D-amino-
propyl-valeric acid (D-APV), have consistently
reduced this activity in the rat dorsal horn nociceptive
neurons, suggesting that the NMDA receptor
contributes to this phenomenon.

59.  Epilepsy is a group of neurological disorders
characterized by spontaneous recurrent seizures.
 A seizure is an abnormal paroxysmal firing of cerebral
neurons in synchronous fashion and is often associated
with motor signs and sensory, autonomic, or psychic
symptoms. Loss or impairment of consciousness often
occurs.
 a prominent feature of most seizures is an abnormal
and excessive firing of glutamatergic neural pathways.
 abnormalities in the regulation of glutamate may be a
factor in the initiation, spread, and maintenance of
seizure activity in some types of epilepsy.

60.  The involvement of glutamatergic receptors in seizures and
epilepsy is widely accepted based on evidence that
injections or focal applications of glutamatergic agonists at
NMDA receptors or AMPA/KA receptors seem to produce
seizures or epileptic-like activity in numerous in vitro and
animal models of epilepsy
 Compounds that antagonize the action of glutamate at
NMDA receptors or AMPA/KA receptors are generally
effective in blocking seizures.
 Many patients with temporal lobe or complex partial
epilepsy are found to have neuronal loss and sclerosis,
particularly in mesial hippocampus.
 .

61.  Dysregulation of glutamate and aspartate and overactivation of their
receptors may contribute to neuronal cell loss in chronic disorders such
as acquired immune deficiency syndrome (AIDS) dementia,
Parkinson's disease, motor neuron disease (including amyotrophic
lateral sclerosis [ALS]), Huntington's disease, and Alzheimer's disease.
 Tissue-specific defects in glial transporter genes resulting in impaired
glutamate uptake (for instance, mutations in the glutamate transporter
GLT1 or EAAT-2) have been identified in several cases of the sporadic
form of ALS.
 Ingestion of β-N-oxalylamino-L-alanine (L-BOAA), a naturally occurring
excitatory amino acid in the chick pea from the plant Lathyrus sativus,
induces neurolathyrism, a progressive form of motor neuron disease
that is clinically similar to ALS. L-BOAA acts as an agonist at the AMPA
receptor.
 In other motor-impairing disorders, abnormal activation of excitatory
pathways within the basal ganglia appears to play a part in the
symptom expression of parkinsonism in animal models.
 In primates, NMDA and non-NMDA antagonists increase the
therapeutic efficacy of the dopaminergic drug levodopa .

62.  Phencyclidine completely blocks NMDA Mg+2 channel
leading to full psychotic spectrum and anterograde
amnesia.
 Ketamine acts as NMDA antagonist blocks hyperactive
glutamate resulting in dissociative analgesia. It is also of
some use in treatment resistant bipolar depression
 Memantine a weak NMDA antagonist that blocks only the
excess glutamate but allows for normal neuronal
transmission is used along with cholinesterase inhibitors in
alzheimer’s disease. Also called artificial Mg+2
 Amantadine an antiviral agent, weak NMDA antagonist,
releaser of dopamine is used in drug indused parkinson’s
and also being tried for bipolar depression.

63.  Ethanol enhances GABA function in VTA and attenuates
NMDA receptor function in VTA
 Chronic abuse causes downregulation of GABA A and
upregulation of NMDA
 Thus during withdrawl there is hyperexcitable state due to
excess glutamate release.
 It can also cause excitotoxicity in wernicke-korsokoff’s
psychosis.
 Acamprosate blocks mGlu5 and mGlu2. also acts indirectly
as NMDA antagonist and agonist to GABA system.
 Club drugs: PCP, ketamine also consumed as drugs.

64.  ALS – loss of EAAT2 in ventral horn
 Autism – mutations in PSD-95 neurexin,
neuroligin,
 Fragile X syndrome – FMRP(Fragile x mental
retardation protein) is involved in dendritic spine
synthesis after NMDA activation. Loss of FMRP
exaggarates mGLUT5 response. mGLUT5
antagonists are being tried for treatment.
 Extinction of conditioned fear in amygdala is by
NMDA receptor activation. D – cycloserine
combined with CBT(cognitive behavioral therapy)
gives better response in treatment of acrophobia.

65.  Excitatory amino acid neuro transmitter.
 Acidic non essential amino acid
 Acts as agonist at glutamate site on NMDA
receptor
 Importance is still under research

66.  GABA (GAMMA AMINOBUTYRIC
ACID

67.  GABA is the major inhibitory amino acid
neurotransmitter
 Has broad distribution in CNS
 It is present in mM concentrations.
 SYNTHESIS: GABA is synthesized from glutamate by
glutamic acid decarboxylase(GAD) ,which catalyzes the
removal of the α-carboxyl group
 GAD is restricted to GABAergic nerve terminals in CNS
and islet cells in periphery
 Two variants GAD65 – synaptic vesicles – seizures.
 GAD67 – neuronal GABA - death,
cleft palate
 GABA released into synapse is reuptaken and
converted by GABA-Transaminase into succinic
semialdehyde which is further converted to succinate
that reenters kreb’s cycle.

68.  In view of its physiological effects and distributions, it is not
surprising that the dysfunction of GABAergic
neurotransmission has been implicated in a broad range of
neuropsychiatric disorders including
 anxiety disorders, schizophrenia, alcohol dependence,
and seizure disorders.
 Chemically, GABA differs from glutamic acid, the major
excitatory neurotransmitter, simply by the removal of a
single carboxy group from the glutamic acid.

70.  In the corticolimbic regions of the brain GABA is localized
to the intrinsic (i.e., local circuit) neurons.
 In the columnar organization of the cerebral cortex, the
GABAergic neurons provide the outer boundaries of the
column with inwardly directed axons.
 While the GABAergic interneurons comprise a minority of
cortical neurons (15–25 percent), they exert a profound
degree of inhibition on the activity of the glutamatergic
pyramidal cells.
 The remarkable efficacy of inhibition reflects two
neuroanatomical features of GABAergic synapses, which
are concentrated on the shafts of spines to mitigate
glutamatergic depolarization and on the neuronal cell
body and proximal axon to restrict the generation of
action potentials.

71.  In the cortex the GABAergic interneurons are the primary
site of colocalization of neuropeptides.
 These include cholecystokinin, dynorphin, neuropeptide Y,
somatostatin, substance P, and vasoactive intestinal
peptide.
 In the striatum, GABAergic neurons project directly to the
substantia nigra pars reticulata, which regulates
dopaminergic neuronal activity.
 In addition, there are striatal GABAergic neurons that
project to the globus pallidus to synapse on pallidal-
subthalamic GABAergic neurons that regulate the excitatory
output from the subthalamic nucleus.
 In the cerebellum, GABAergic Purkinje cells are its main
efferent system.

72.  Two major classes
1. GABAA receptors
2. GABAB receptors
 Minor class
1. GABAC receptors

73.  Ligand gated chloride channel
 Heteropentameric glycoprotein channel.
 Causes influx of chloride in mature neurons ----
hyperpolarisation.
 May cause efflux in immature neurons ----
depolarisation .
 (In immature neurons, which have unusually high levels of intracellular Cl-,
activating the GABAA receptor can counterintuitively cause depolarization.
 For this reason, anticonvulsants that act by enhancing GABAA receptor
activity may actually exacerbate seizures in the neonatal period.)
 SUBUNITS: α,β,γ,δ,ε which are further classified
into 18 subtypes
 GABA binds between α and β

74.  Benzodiazepine sensitivity: presence of 2 beta+
1gamma (γ2/γ3) + 2alpha(α1/α2/α3) makes a
GABA A receptor BDZ sensitive. BDZ binds in
between alpha and gamma subunits.
 They are post synaptic cause phasic inhibition
associated with bursts of GABA release
 Alpha1 ---- anticonvulsant, sedative, amnestic
 Alpha2 ---- anxiolytic, muscle relaxant( in cortex and
hippocampus)
 Benzodiazepine insensitive GABA A receptors have
α4,α6,γ1,δ subunits, located extra synaptically and
cause tonic inhibition --- implicated in anxiety.

76. Site name Action mechanis
m
Importance
GABA
binding
Muscimol Full
agonist
GABA
binding
bicuuline antagoni
st
freq. and
duration
proconvulsant
Picrotoxi
n site
picrotoxin antagoni
st
Block
chloride
channel
proconvulsant
BDZ site BDZ PAM Increase
freq
Sedative,
anxiolytic,
BDZ site flumanezil NAM BDZ toxicity
Rx
Other
sites
barbiturate
s
PAM Increase
GABA
affinity
anticonvulsant
ethanol,
general
anesthetics,
neurosteroi
ds
PAM

77.  Z drugs(zolpidem, zaleplon, zopiclone) bind to non
BDZ site act as PAMs and improve insomnia.
 Chemically modified progesterone and
corticosterone have sedative and anxiolytic
effects
 Penicillins at high dose occlude chloride channel
 General anesthetics increase chloride
conductance and inhibit neurotransmission.
 Ethanol increases response of tonic GABA
activated currents in delta containing receptors
 GABA C is a voltage gated chloride channel
similar to GABA A with as yet unknown functions.

78.  The GABAB receptors are distinguished pharmacologically from
GABAA receptors by they are insensitive to the canonical GABAA
receptor antagonist bicuculline and that they are potently
activated by baclofen [β-(4-chlorophenyl)-γ-aminobutyric acid],
which is inactive at GABAA receptors.
 They are members of the G-protein coupled superfamily of
receptors but are highly unusual as they are made of a dimer of
two seven-transmembrane-spanning subunits.
 GABAB receptors are widely distributed throughout the nervous
system and are localized both pre- and postsynaptically.
 The postsynaptic GABAB receptors cause a long-lasting
hyperpolarization by activating potassium channels.
 Presynaptically, they act as auto- and heteroreceptors to inhibit
neurotransmitter release.

79.  The GABAB receptors generally exert an inhibitory
effect on neuronal excitability by generating
hyperpolarizing potentials that are much slower (slow
IPSPs) in onset and longer in duration than those
mediated by GABAA receptors.
 GABAB receptors are GPCRs and activate a type of K+
channel, thereby hyperpolarizing the membrane.
 GABAB receptors are often located on presynaptic
terminals, where they serve to inhibit transmitter
release by reducing the ability of action potentials to
activate Ca2+ influx.

80.  SCHIZOPHRENIA:
 Reduction in GABAergic interneurons in
cortex along with decreased expression of
GAD67, parvalbumin, and upregulation of
GABA A imply GABA hypofunction
 These can be replicated by chronic
treatment with NMDA antagonists which
cause destruction of interneurons causing
disinhibition of pyramidal output leading to
cognitive and affective symptoms.

81.  Decreased GABAergic transmission in
prefrontal cortex in MDD.
 Decrased levels of neurosteroids in CSF
and plasma.
 Estrogen exerts cyclical inhibition on
GABA interneurons causing disinhibition
of pyramidal neurons leading to LTP.
 High incidence of depression in women
during high estrogen states.

82.  Valproate --- stimulates GAD
 Tigabine -- GAT1 inhibitor
 Vigabatrin – GABA Transaminase inhibitor
 Valproate --- SSADH(succinate semialdehyde
dehydrogenase) inhibitor
 Gabapentin, pregabilin – facilitate GABA release
 Gabapentin – GABA agonist
 Barbiturates --- GABA enhancer
 Benzodiazepines -- PAMs GABA facilitators
 Topiramate --- enhance post synaptic GABA A
currents.

83.  Shift in GABA A receptor set point in agonist spectrum. Consider
antagonist as inverse agonist
 BDZs enhance GABA A phasic inhibition of fear associated output
from amygdala
 NOVEL ANXIOLYTICS:
 Partial agonists at alpha 2/3 subtype of GABA A receptor cause
anxiolysis without sedation
 Tigabine GAT1 inhibitor has anxiolytic effect

84.  GABA neurons from VLPO(ventro lateral preopic
nucleus)(sleep promoter) project to TMN(tubero mamillary
nucleus)(wake promoter) thus inhibiting TMN and causing
sleep.
 In thalamic filter CSTC loop, GABA neurons from striatum to
thalamus maintain the thalamic filter and prevent excess
sensory data to reach cortex.
 When GABA decreases, thalamic filter fails causing hyper
aroused state.
 GABA A PAMs the Z drugs(zolpidem, zaleplon, zopiclone)
promote GABA interneuron inhibition of pyramidal output at
cortex as well as the thalamic filter thus causing sleep
 They also have alpha 1 selective action which decreases the
chance of dependence, abuse potential.

86.  Genetic susceptibility to alcoholism:
 GABA Aα2 is associated with impulsivity
 GABA Aα6 is associated with low response to
alcohol hypothesis.
 Ethanol at concentrations associated with
intoxication has a dual action of enhancing
GABAergic receptor function and attenuating NMDA
receptor function.
 The GABA receptor effects may be associated with
the anxiolytic effects of ethanol

87.  Persistent abuse and dependency on ethanol result in a
downregulation of GABAA receptors and an upregulation
of NMDA receptors such that acute discontinuation of
ethanol results in a hyperexcitable state characterized
by delirium tremens.
 Furthermore, supersensitive NMDA receptors in the
context of thiamine deficiency may contribute to the
excitotoxic neuron degeneration of Wernicke–Korsakoff
syndrome.
 Acamprosate is a derivative of homotaurine that was
developed as an agent to reduce alcohol consumption,
craving, and relapse in alcoholic patients.
 Because of taurine's resemblance to GABA, it was
thought that acomprosate acted via GABAA receptors

88.  Fetal alcohol syndrome is the most common preventable
cause of mental retardation.
 Convincing evidence has been developed that the
microencephaly associated with fetal alcohol exposure
results from inhibition of NMDA receptor function,
resulting in widespread neuronal apoptosis in the
immature cortex.
 NMDA receptor activation is essential for immature
neuronal survival and differentiation

89.  Loss of spinal and supraspinal inhibition may result in
spasticity or hyperreflexic states.
 One particular disorder, stiff person syndrome, is
associated with increased reflexivity, muscle rigidity,
episodic muscle spasms, and, occasionally, seizures,
diabetes, or both.
 The disorder is frequently associated with circulating
antibodies to glutamate decaroxylase(GAD), the
GABA synthesis enzyme.
 Benzodiazepines, especially diazepam, and baclofen
are mainstays in the treatment of spasticity. However,
these agents are often only moderately effective,
especially in supraspinal forms of spasticity

90.  the GABAA α5 subunit that is predominantly
located in the hippocampus is involved in cognitive
processing, and abnormalities of this subunit may
be involved in cognitive deficits and bipolar
disorders.
 Abnormalities in the GABAA receptor β3 subunit
could be involved in anxiety and depressive
disorders and insomnia.

92.  Glycine is an inhibitory neurotransmitter primarily in the brainstem and spinal cord,
although the expression of glycine receptor subunits in the thalamus, cortex, and
hippocampus suggest a broader role.
 SYNTHESIS
1. Glycine is a nonessential amino acid that is synthesized in the brain from L-
serine by serine hydroxymethyltransferase.
2. Also synthesized from glyoxalate by D –glycerate dehydrogenase
 TRANSPORTERS:
1. Glycine is concentrated within synaptic vesicles by H+-dependent vesicular
inhibitory amino acid transporter (VIAAT or VGAT), which also transports GABA.
2. GlyT1 ---- in the astrocytes surrounding NMDA receptors for reuptake of
glycine.
3. GlyT2 ----- in the presynaptic glycine neurons
 Termination of the synaptic action of glycine is through reuptake into the presynaptic
terminal by the glycine transporter II (GlyT2), which is quite distinct from GlyT1 that
is expressed in astrocytes and modulates NMDA receptor function.

93.  RECEPTORS:
 The receptor was first identified through the specific
binding of strychnine.
 Glycine binds to two sites: One that is displaceable
by strychnine and represents the glycine A receptor
and a second that is insensitive to strychnine and is
designated the glycine B receptor, representing the
glycine modulatory site on the NMDA receptor.
 Glycine A receptor -- pentameric chloride channel
strychnine sensitive spinal cord
α ,β subunits.
 Agonists -- β-alanine, taurine, L-alanine, L-serine,
GABA
 Antagonist – strychnine.

94.  Hyperekplexia is a disorder due to mutations in
genes encoding components of the glycinergic
synapse. It is characterized by stiffness and
excessive startle in infancy that subsides with
maturation. Mutations causing hyperekplexia have
been described in the α subunit (GLRA1) and in the β
subunit (GLRB) of the glycine receptor but also in
GlyT2 (SLC6A5).

95.  Comprehensive text book of psychiatry 9th
edition
 Comprehensive text book of psychiatry 8th
edition
 Stahl’s essential psychopharmocology 3rd
edition
 Internet

96. Thank you