NEUROTRANSMITTERS final presentation-1-1.pptx

NEUROTRANSMITTERS
IMPLICATED IN PSYCHIATRY
MENTOR- Dr. Lokesh Shekhawat Sir.
PRESENTOR- Dr. Vibha Tomar.

CONTENT OF PRESENTATION
• Introduction
• Classification of neurotransmitter
• Individual neurotransmitter
 Dopamine
 Serotonin
 Norepinephrine
 Epinephrine
 Acetylcholine
 Histamine
 GABA
 Glutamic acid
 EndorphinS
 Endocannabinioids

INTRODUCTION
• Paramount functional property of nerve cells is their ability to receive, conduct
and store information
• Signal transmission between neurons occurs at specialized junctions, referred to as
synapses
Chemical synapses
Electrical synapses
• Signal transmission between chemical synapses involves the release from
presynaptically located sites of neuroactive molecules (neurotransmitter or
neuromodulator) which bind to receptors in the membrane of the target cell, the
postsynaptic membrane.(Halbach etal., 2006).

• Neurotransmitters are the most common class of chemical messengers in the
nervous system. A neuroactive substance has to fulfill certain criteria before it can
be classified as a neurotransmitter (Werman etal., 1966).
1. It must be of neuronal origin and accumulate in presynaptic terminals, from
where it is released upon depolarization.
2. The released neurotransmitter must induce postsynaptic effects upon its
target cell, which are mediated by neurotransmitter-specific receptors.
3. The substance must be metabolically inactivated or cleared from the
synaptic cleft by re-uptake mechanisms.
4. Experimental application of the substance to nervous tissue must produce
effects comparable to those induced by the naturally occurring
neurotransmitter.

• A neuromodulator, as the name implies, modulates the response of a neuron to a
neurotransmitter.(Halbach etal., 2006).

DOPAMINE
Five key dopamine pathways in the brain.
1. Mesolimbic .
2. Mesocortical .
3. Nigrostriatal.
4. Tuberoinfundibular.
5. Fifth pathway that innervates the thalamus.
( Stahl’s essential psychopharmacology 4th edition)

Dopamine receptors
D1 Like D2 Like
1) D1 & D5 D2,D3 & D4
2) Increases adenylate cyclase activity via
Gs receptors.
Inhibits adenylate cyclase activity via Gi
receptors.
3) Postsynaptic in location Both presynaptic and postsynaptic in
location.
4) Present in high density nigrostriatal,
mesolimbic & mesocortical areas.
More evenly distributed, highest level in
striatum & nucleus accumbens.

Dopamine hypothesis of schizophrenia

Nigrostriatal Pathway- substantia nigra to dorsal
striatum.
• Part of the extrapyramidal nervous system,
and controls motor movements.
• Dysfunction cause movement disorders
including Parkinson’s disease, characterized by
rigidity, akinesia/bradykinesia and tremor.
• DA deficiency in basal ganglia also can
produce akathisia and dystonia.
These movement disorders can be replicated by drugs
that block D2 receptors in this pathway, stahls

Tuberoinfundibular pathway
these neurons are tonically active and
inhibit prolactin release. Activity
decreased in
• Lactation
• Lesions
• Antipsychotic drugs that block
D2 receptors
Elevated prolactin levels are
associated with galactorrhea (breast
secretions), amenorrhea (loss of
ovulation and menstrual periods), and
sexual dysfunction.
stahls

Dopamine and substance use disorder.
CTP

SEROTONIN
• Cell bodies clustered in multiple midline raphe nuclei of the brainstem.
• Caudal raphe nuclei
send descending projections to medulla, cerebellum, and spinal cord which.
involved in motor activity, pain control, and regulation of autonomic
processes.
• Rostral dorsal and median raphe nuclei send ascending axonal projections.
Median raphe innervates the limbic system.
Dorsal raphe innervate the cerebral cortex, thalamus, striatum along with the
dopaminergic neurons in substantia nigra and VTA.
modulatory role in many functions including mood, anxiety, aggression,
cognition, feeding, the sleep–wake cycle, and sexual behavior.
(CTP )

RECEPTOR SUBTYPES LOCATION CLINICAL IMPLICATION
5HT1 5HT1A
Wide distribution
Presynaptic- autoreceptor
Postsynaptic, astrocytes and glia.
Partial agonists (buspirone)used as
anxiolytics.
5HT1B & 5HT1D Pre >>> post- autoreceptors
5HT1B Heteroreceptors.
1B&1D agonists (triptans) used in
migraine.
5HT1E - May have role in memory disorder.
5HT1F - May have role in migraine
5HT2 5HT2A Cortical pyramidal & interneurons. Target of hallucinogens (agonists),
2nd generation antipsychotics
(antagonists), SSRIs
(downregulation)
5HT2B Restricted expression Under research, cardiotoxic.
5HT2C Heterogenous Antipsychotic induced weight gain,
Regulate release of DA neuron in
VTA

RECEPTOR SUBTYPES FUNCTION CLINICAL IMPLICATION
5HT3 - Both pre &post. ( medulla & spinal
cord. Presynaptic- heteroreceptors
Anatgonists used as anti-
emetic in emesis a/w
cancer chemoRx &
radioRx’
5HT4 - Upper GI motility. Gastroprokinetic.
5HT6 & 5HT7 - Postulated in cognitive function. Under resersch.

Serotonin &
psychotic disorder
Cortical 5HT2A- reduces
DA release.

5HT2A antagonistic
action of antipsychotics.
low eps &
hyperprolactinemia

SEROTONIN & ANXIETY DISORDER.
• Serotonin is a key neurotransmitter that innervates the amygdala as well as all the
elements of CSTC circuits, namely, prefrontal cortex, striatum, and thalamus, and
thus is poised to regulate both fear and worry.
• Antidepressants that can increase serotonin output by blocking the serotonin
transporter (SERT) are also effective in reducing symptoms of anxiety and fear.
• A serotonin (5HT1A) partial agonist, buspirone, is recognized as a generalized
anxiolytic.

Nor- epinephrine
• The norepinephrine (“noradrenergic”) innervation in brain mainly derives from
neurons located in the locus coeruleus (LC, part of the pons) and the lateral
tegmental area (part of the midbrain).
• LC neurons primarily target the forebrain, thalamus, cerebellum, and spinal cord
• the lateral tegmental neurons send fibers to the hypothalamus and basal forebrain.
• LC norepinephrine neurons exhibit different activity modes: tonic firing with short
periods of burst firing. Alterations in the tonic mode associated with the sleep–
waking cycle, whereas the phasic mode occurs in response to arousing stimuli.
• There is an important role of LC norepinephrine neurons in vigilance, attention,
and working memory.
(CTP )

Adrenergic receptors.
• Adrenergic receptors divided into two classes α and β.
• α has subtypes α1-receptor (α1a, α1b, α1d) & α2-receptor subtypes (α2A–D).
• β-receptor subtypes (β1–3).
• α1- and β-receptors typically postsynaptic .
• α2-receptors exist both pre- and postsynaptic .

NORADRENALINE & MOOD
DISORDER.

NORADRENALINE, DOPMAINE & ADHD

NORADRENALINE & ANXIETY DISORDER.
• Norepinephrine is another neurotransmitter with important regulatory input to the
amygdala and prefrontal cortex and thalamus in CSTC circuits.
• Excessive noradrenergic output from the locus coeruleus result in peripheral
manifestations of autonomic overdrive, also trigger central symptoms of anxiety
and fear, such as nightmares, hyperarousal states, flashbacks, and panic attacks.
• Symptoms of hyperarousal such as nightmares can be reduced in some patients
with α1-adrenergic blockers such as prazocin.
• Symptoms of fear and worry can be reduced by norepinephrine reuptake inhibitors
(also called NET or norepinephrine transporter inhibitors).

Glutamate
• Major excitatory neurotransmitter in the central nervous system.
• Neurotransmitter for approximately 80 percent of brain synapses
• “Master switch” of the brain.
• A key theoretical role in the hypothesized pathophysiology of schizophrenia & in a
number of other psychiatric disorders, including depression. (stahl’s)
• Due to excitatory effects of glutamate, it is excluded from the brain by the BBB.

Glutamate receptors
1. Ligand-gated ion channels.
NMDA (N-methyl-d-aspartate)
AMPA (α-amino3-hydroxy-5-methyl-4-isoxazole-propionic acid)
 Kainate receptors.
2. Metabotropic glutamate receptor GPCRs, primarily modulate glutamatergic
neurotransmission.
group II and group III metabotropic receptors can occur presynaptically,
autoreceptors.
Group I predominantly postsynaptically, facilitate and strengthen
responses mediated by ligand-gated ion-channel receptors.

NMDA receptors
• At rest they are inactive, calcium channel blocked by magnesium plug.
• “Coincidence receptors”
• Open to trigger postsynaptic actions only when three things occur at the same
time:
1. glutamate occupies its binding site on the NMDA receptor
2. glycine or d-serine (co-transmitters) binds to its site on the NMDA
receptor,
3. depolarization occurs, allowing the magnesium plug to be removed.

• Key glutamate pathways in the brain.
Cortico-brainstem
Cortico-striatal
Hippocampal-striatal
Thalamo-cortical
Cortico-thalamic
Cortico-cortical (direct)
Cortico-cortical (indirect)

Glutamate & Schizophrenia
• NMDA hypofunction hypothesis of schizophrenia with the dopamine hypothesis
of schizophrenia : positive symptoms
1. cortico-brainstem glutamate neurons regulate mesolimbic DA system (VTA
to the nucleus accumbens-direct pathway).
2. Hippocampal glutamate neurons regulate mesolimbic DA system via a four-
neuron circuit.

• NMDA hypofunction hypothesis of schizophrenia with the dopamine
hypothesis of schizophrenia : negative symptoms
• Cortico-brainstem glutamatergic neurons regulate mesocortical DA system
indirectly via an inhibitory GABA interneuron.

• Gabapentin and pregabalin, also known as α2δ ligands, since they bind to the α2δ
subunit of presynaptic N and P/Q VSCCs, block the release of excitatory
neurotransmitters such as glutamate when neurotransmission is excessive, as
postulated in the amygdala to cause fear and in CSTC circuits to cause worry.
• Glutamate also has role in learning & memory- has been seen in neurophysiological
studies as plasticity in glutamatergic neurotransmission [phenomena of long-term
potentiation (LTP) and long-term depression (LTD)] in glutamatergic pyramidal
neurons in hippocampal cortex.
(CTP )

GLUTAMATE IN ALCOHOL USE DISORDER
• Alcohol’s mechanism of action it enhances inhibition at GABA synapses and
reduces excitation at glutamate synapses.
• Alcohol acts at presynaptic metabotropic glutamate receptors (mGluRs) and
presynaptic voltage sensitive calcium channels (VSCCs) to inhibit glutamate
release.
• Alcohol at GABA synapses enhance GABA release via blocking presynaptic
GABAB receptors, and also directly stimulate postsynaptic GABAA receptors,
especially those of the δ subtype that are responsive to neurosteroid modulation.

GABA (γ-aminobutyric acid)
• Principal inhibitory neurotransmitter in the brain
• Important regulatory role in amygdala and CSTC loops, so it’s key
neurotransmitters involved in anxiety
• Target of many anxiolytic drugs used to treat the spectrum of anxiety
disorders.

GABAA GABAB GABAC
Ligand gated ion channels. GPCRs. Ligand gated ion channels.
Implicated in anxiety, sleep &
alcohol use disorder.
Implicated in pain, memory &
mood disorders.
-
Targets of benzodiazepines,
barbiturates, sedative hypnotics &
alcohol.
Target of GHB (γ-Hydroxybutyrate
(GHB), approved for the treatment
of narcolepsy.
-

Benzodiazepine insensitive GABAA Benzodiazepine sensitive GABAA
Composition- α4, α6.
γ1, or δ subunits.
Composition α1, α2, or α3.
γ2 or γ3 subtype subtype.
Location- Extrasynaptic. Postsynaptic.
Mediate- Tonic inhibition of postsynaptic neurons. Phasic inhibition of postsynaptic neuron.

• Benzodiazepine-sensitive GABAA receptors with α1 subunits may be most
important for regulating sleep.
• Benzodiazepine-sensitive GABAA receptors with α2 (and/or α3) subunits may be
most important for regulating anxiety
• ongoing search for selective α2/3 agents that could be utilized to treat anxiety
disorders without being sedating.
• Partial agonists selective for α2/3 subunits of benzodiazepine sensitive GABAA
receptors hypothetically would cause less euphoria, be less reinforcing and thus
less abusable, cause less dependence, and cause fewer problems in withdrawal.

ACETYLCHOLINE
Cholinergic neurons either project to distant targets or contact cells locally within
the same region (interneurons).
cholinergic neurons cell bodies clustered
1) mesopontine complex in the upper brainstem-projects to PFC, basal forebrain,
thalamus, hypothalamus, amygdala & hippocampus
2) basal forebrain complex- PFC, amygdala & hypothalamus.

• Nicotinic Receptors.
Ligand-gated ion channels
Located at the neuromuscular junction, autonomic ganglia, adrenal medulla,
brain, and spinal cord.
Role of neuronal nicotinic acetylcholine receptors is in mediation of
reinforcing and addicting properties of nicotine in chronic tobacco and e-
cigarette users.
The reinforcing effects of nicotine via nicotinic receptors in the brain’s reward
system (VTA and nucleus accumbens DA pathway).

• Muscarinic receptors (M1 to M5)
All are present in brain & are GPCRs.
M1, M3, and M4 are primarily located in cerebral cortex and hippocampus,
role in learning and memory.
High densities of M1 and M4 are located in striatum and mediate cholinergic
signaling in extrapyramidal motor circuits and response to rewards.
M2 concentrated in the basal forebrain, function as autoreceptors .
M5 receptor is expressed at low levels in brain.

• Implication of acetylcholine is in Alzheimer disease there is significant
degeneration of neurons in the nucleus basalis, leading to substantial reduction in
cortical cholinergic innervation.
• The extent of neuronal loss correlates with degree of dementia, and the cholinergic
deficit may contribute to the cognitive decline in this disease, consistent with the
beneficial effects of drugs that promote acetylcholine signaling in this disorder.
( CTP )

HISTAMINE
• Histamine-containing neuronal cell bodies are restricted to the tuberomammillary
complex of the posterior hypothalamus.
• Provide diffuse projections to many telencephalic, mesencephalic, and cerebellar
structures.
• Functions- regulation of sleep and arousal, and control of feeding and appetite.
• In the periphery, histamine released from mast cells plays an important role in the
allergic reactions & histamine released from enterochromaffin-like cells and mast
cells stimulates acid secretion in the stomach.
( CTP )

• Four subtypes of histamine receptors (H1 to H4)
• G-protein–coupled receptors
• H1 and H2 receptors are expressed both in neurons postsynaptic to histamine
terminals and also in glia.
• Blockade of H1 receptors results in sedation, a side-effect inherent in some
antipsychotic drugs, and allergy medications, such as diphenhydramine .
• H3 receptors located presynaptically
autoreceptors, inhibit the release of histamine.
H3 receptors are also present as heteroreceptors on terminals of other
neurotransmitters to regulate their function

• Recently a selective inverse agonist at the H3 receptor, pitolisant, has been shown
to be effective at countering excessive diurnal sleepiness in narcolepsy, Parkinson
disease, and obstructive sleep apnea.
• Antagonists and inverse agonists for the H3 receptor have potential as treatments
for cognitive disorders. H4 receptors are present at low levels in brain.
( CTP )

ENDORPHINS
• The term endorphin refers to a subclass of opioid like substances, consisting of
peptides produced naturally by human body, includes dynorphins, enkephalins,
endorphins, endomorphins, and nociception.
• Opioid receptors are G protein-coupled receptors (GPCRs) with opioids as ligands
and respond to endogenous opioids (endorphins).
• The opioid receptors are distributed widely in the brain, the spinal cord, and digestive
tract. There are four currently known types of opioid receptors, delta (δ), kappa (κ),
mu (μ), and nociceptin receptor (NOP).
• Mu receptors are preferentially activated by betaendorphin and are largely responsible
for the constellation of effects classically associated with morphine-like drugs:
analgesia, euphoria, cough suppression, respiratory suppression, pupillary
constriction, and (via receptors in the gut) constipation.
(CTP )

• Delta receptors are preferentially activated by enkephalins. Delta agonists do
produce effects like anxiolytic and antidepressant-like effects, along with
proconvulsant effects and only limited efficacy for analgesia.
• Kappa receptors are preferentially activated by dynorphin. Kappa agonists,
produce a distinct effects, most notably “prodepressant” and aversive effects,
correspond to dysphoria and psychotomimesis.
( CTP )

Endocannabiniods
• In 1992 when Mechoulam and colleagues reported the discovery of anandamide, a
lipid produced endogenously in the brain that could activate cannabinoid receptors
and function as a neurotransmitter
• Several additional endocannabinoids were soon discovered: 2-arachidonylglycerol
(2-AG), N-arachidonyldopamine (NADA), 2-arachidonoylglycerol ether (noladin
ether), and virodhamine
• Anandamide have greatest selectivity for the CB1 receptor, followed by NADA
and noladin ether.
• virodhamine prefers CB2 receptors and has only partial agonist activity at CB1. 2-
AG appears not to discriminate between CB1 and CB2.
( CTP )

• Arachidonic acid building block for biosynthesis of endocannabinoid.
• Endocannabinoids are not stored in synaptic vesicles for later use, but are
synthesized on demand as is done for the gaseous neurotransmitters.
• CB1 receptors possibly most abundant GPCRs in the brain.
• Highest density in the basal ganglia, cerebellum, hippocampus, hypothalamus,
ACC, and cerebral cortex, particularly the frontal cortex.
( CTP )

• action of cannabinoids in the basal ganglia and cerebellum may prove relevant in
understanding catatonic symptoms in schizophrenia.
• CB1 receptors localized presynaptic rather than postsynaptic side of the neuronal
cleft, suggesting a role in regulation of neurotransmission.
• cannabinoids have been shown to block the release of a variety of
neurotransmitters, including GABA, norepinephrine, and acetylcholine.
• Norepinephrine and acetylcholine excitatory neurotransmitters, and cannabinoid
inhibition would have an inhibitory effect.
(CTP )

• GABA inhibitory neurotransmitter, and cannabinoid inhibition of it would lead to
excitatory effects, demonstrating that cannabinoids can have complex effects on
neurotransmission.
• Cannabinoids also appear to increase the release of brain endorphin
neurotransmitters and increase dopamine release in the nucleus accumbens, a
“reward center” relevant to addiction and learning.
• The endocannabinoids have been implicated in a variety of forms of synaptic
plasticity, including LTP and LTD.
• synthesis of endocannabinoids predominantly postsynaptic which suggests
retrograde regulation presynaptic neuron.
( CTP )

NEUROTRANSMITTERS final presentation-1-1.pptx

Recommended

Recommended

More Related Content

Similar to NEUROTRANSMITTERS final presentation-1-1.pptx

Similar to NEUROTRANSMITTERS final presentation-1-1.pptx (20)

More from ASHISH KUMAR

More from ASHISH KUMAR (12)

Recently uploaded

Recently uploaded (20)

NEUROTRANSMITTERS final presentation-1-1.pptx