Aminoacid neurotransimitter

96
AMINOACID NEUROTRANSIMITTERS DR.V.L.NARASIMHA SEKHAR 1 ST YEAR PG DEPT OF PSYCHIATRY SVRRGGH

Transcript of Aminoacid neurotransimitter

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AMINOACID NEUROTRANSIMITTER

SDR.V.L.NARASIMHA SEKHAR

1ST YEAR PGDEPT OF PSYCHIATRY

SVRRGGH

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HISTORY

Ramón y Cajal

 The father of modern neuroscience

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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.

The 18th and 19th C debate about the nature of communication in the nervous system:Electrical or Chemical??

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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,

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 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.

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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.

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Criteria to be labelled as Neurotransmitter

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)

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CLASSES OF NEUROTRANSIMITTER

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Table 1. Classes of CNS Transmitters

Neurotransmitter % of Synapses

BrainConcentration

Function Primary Receptor Class

Monoamines Catecholamines : DA, NE, EPIIndoleamines: 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 acidsInhibitory: 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

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(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.

Criteria used to identify an amino acid as a neurotransmitter

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GLUTAMIC ACID

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Glutamic acid/ glutamate 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.

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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.

GLUTAMATE

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SYNTHESIS Glutamate is excluded from BBB and is

synthesized denovo from 1. Glucose via krebs cycle2. Glutamate recycling called glutamine cycle.3. Aspartate4. α- oxo glutarate

Of these 40% of glutamate for neurotransmission is obtained via recycling by glutamine cycle.

20% from glucose through kreb’s cycle.

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Glutamate fast neurotransmissionSynthesis, packaging, reuptake, degradation

(error - should be EAAT)

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TRANSPORTERS 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.

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Vesicular glutamate transporters VGLUTs are expressed in presynaptic neuron

for transport of glutamate into vesicles once it is synthesized

These are 3 types:1. VGLUT1 - cortex2. VGLUT2 – diencephalon, brainstem3. VGLUT3 – co-transmitter in non glutamatergic

neurons.

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PATHWAYS 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

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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.

Major Glutamatergic Pathways in the Brain

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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) receptors2. metabotropic receptors (mGluR)

Glutamate receptors

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TYPES OF GLUTAMATE RECEPTORS

Ionotropic receptors Metabotropic

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NMDA receptor 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

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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.

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Conducts mainly Ca+2.

Also called coincidence detector Activation requires simultaneous

occurrence of 3 events.1. Depolarisation by AMPA receptor –

removes Mg+2 blockade2. Binding of co-transmitter glycine / D –

serine3. Binding of 2 glutamate4. Results in Ca+2 conductance 5. activates protein kinase6. Leads to gene expression mainly c-fos

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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.

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Regulation 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

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AMPA receptors 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.

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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.

AMPA Receptors

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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.

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Clinical implications 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

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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.

Kainate Receptors

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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

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Metabotropic receptors

Group Sub units Receptor

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.

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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

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Importance 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.

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Agonists and antagonists

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Memory NMDA receptor activation in hippocampal CA1

pyramidal cellRelease of Ca+2

Activation of kinases/ phosphatasesCaMKII +NMDA receptor complex

HyperphosphorylationIntegration of new AMPA receptors into post

synaptic membraneLong term potentiationNew memory formation

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SchizophreniaNMDA receptor hypofunction hypothesis

5 glutamte pathways relevant in schizophrenia: 1. Corticobrainstem 2. Corticostriatal3. Thalamocortical4. Corticothalamic5. Corticocortical

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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.

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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.

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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.

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Neurodegenerative hypothesis

The neurodegenerative events in schizophrenia may be because of excitotoxicity.

Chronic irreversible deterioration in cognitive functions is hypothesized to be because of excitotoxicity.

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Excess NMDA receptor activation positive symptoms

Overactivation excess Ca+2

Excess enzyme activation free radicals

Dendrite destruction

Neuronal death negative, cognitive affective symptoms

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Neurodevelopmental hypothesis

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 are1. BDNF(brain-derived neuropathic factor) – a trophic

factor2. Dysbindin – formation of synaptic structures3. Neuregulin - neuronal migration, myelination4. DISC 1(Disrupted in scizophrenia)gene – neurogenesis,

migration and dendritic organisation.

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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.

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Newer antipsychotics 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.

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Mood disorder. 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

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Excitotoxicity 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

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Necrosis Apoptosis

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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.

Neuropathic Pain

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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.

Epilepsy

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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.

.

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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 .

Chronic Neurodegenerative Disorders

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NMDA ANTAGONISTS 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.

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ALCOHOL reactive reward system 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.

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Other disease associated with glutamate 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.

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ASPARTATE Excitatory amino acid neuro transmitter. Acidic non essential amino acid Acts as agonist at glutamate site on NMDA

receptor Importance is still under research

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GABA (GAMMA AMINOBUTYRIC ACID

INHIBITORY AMINOACID NEUROTRANSMITTER

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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.

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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.

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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.

Anatomy of GABAergic Systems

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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.

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Two major classes1. GABAA receptors2. GABAB receptors

Minor class1. GABAC receptors

GABA RECEPTORS

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GABA A receptor 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

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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.

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Site name Action mechanism

Importance

GABA binding

Muscimol Full agonist

GABA binding

bicuuline antagonist

freq. and duration

proconvulsant

Picrotoxin site

picrotoxin antagonist

Block chloride channel

proconvulsant

BDZ site BDZ PAM Increase freq

Sedative, anxiolytic,

BDZ site flumanezil NAM BDZ toxicity Rx

Other sites

barbiturates

PAM Increase GABA affinity

anticonvulsant

ethanol, general anesthetics, neurosteroids

PAM

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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.

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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.

GABAB Receptors

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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.

GABAB Receptors

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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.

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MOOD DISRDERS 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.

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ANTI CONVULSANT / MOOD STABILISERS 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.

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ANXIETY 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

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SLEEP 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.

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Substance abuse - GABA 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

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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

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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

Fetal alcohol syndrome

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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

Spasticity

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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.

Other Conditions

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GLYCINE

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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.

SYNTHESIS1. 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.

Glycine as a Neurotransmitter

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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 cordα ,β subunits.

Agonists -- β-alanine, taurine, L-alanine, L-serine, GABA

Antagonist – strychnine.

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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).

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Comprehensive text book of psychiatry 9th edition

Comprehensive text book of psychiatry 8th edition

Stahl’s essential psychopharmocology 3rd edition

Internet

REFERANCES

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Thank you