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The basic processes of synaptic transmission in the
4 processes occur in relation to nerve transmission in CNS:
1)Neurotransmitters – Neurotransmitters are chemical messengers that transmit signals
from a neuron to a target cell across a synapse. They are synthesized in presynaptic
and are released into synaptic cleft to rapidly stimulate or inhibit postsynaptic neurons fast
neurotransmitters operate through ligand-gated ion channels, slow neurotransmitters
operate through G-protein-coupled receptors
2)Neuromodulators – are released by neurons and astrocytes to produce slower pre-or
postsynaptic responses (eg. Carbon dioxide, locally released adenosine, some purines,
peptides, prostaglandins, arachidonic acid metabolites and Nitric oxide)
3)Neuromediators – are second messengers that play crucial role in elicitation of postsynaptic
responses produced by neurotransmitters (eg. cAMP, cGMP and inositol phosphate)
4)Neurotropic factors – are mainly released by CNS neurons, astrocytes and microglia and act
longer than neuromodulators to regulate the growth and morphology of neurons and control
long-term changes in brain (synaptic plasticity, remodeling, phenotype characteristics) mainly
by affecting gene transcription by acting through tyrosine kinase-linked receptors (eg.
Cytokines, chemokines, growth factors.)
THE CHANGE IN ELECTRICAL POTENTIAL
ASSOCIATED WITH THE PASSAGE OF AN
IMPULSE ALONG THE MEMBRANE OF A
MUSCLE CELL OR NERVE CELL.
• Resting Potential
• Sodium and potassium channels are closed. Na+ rush into the cell; K+ are
concentrated inside the cell. Potential difference: -85 mV.
• Sodium channels open in response to a stimulus. Na+ rush into the cell
according to the dictates of diffusion. Final potential difference +30 mV.
• Na+ channels close and K+ channels open. K+ rush out of the cell according to the
dictates of diffusion. Potential difference: slightly below -85 mV.
• Hyperpolarization is a change in a cell's membrane potential that makes it more
negative. It is the opposite of a depolarization. It inhibits action potentials by increasing
the stimulus required to move the membrane potential to the action potential
• Resting Conditions Re-established
• Na+ and K+ channels are closed. Sodium-potassium exchange pump moves
Na+ out and K+ in. Resting potential difference: -85 mV.
WHEN A NEUROTRANSMITTER BINDS: THE
• Voltage change at receptor site –
postsynaptic potential (PSP)
• Changes the probability of the
postsynaptic neuron firing
• Positive voltage shift – excitatory
PSP (decreases the negativity of the
inside of the neuron with respect to
• Negative voltage shift – inhibitory
PSP (increases the negativity of the
inside of the neuron)
Metabolism and reuptake
Drug related to dopamine system
Disease and its treatment
• It is the most important of the biogenic amine neurotransmitters
• Dopamine appears to be an inhibitory neurotransmitter
• Dopamine belongs to the family of catecholamines. Hormones,
Epinephrine and Norepinephrine (other catecholamines) are
derived from Dopamine
• Plays an important role in the regulation of motor functions,
initiation of behavioural patterns and modulation of visceral
functions Dopamine is particularly important in relation to
neuropharmacology (Parkinson's disease, schizophrenia –
hyperdopaminergic state, attention deficit disorder, substance
abuse, endocrine disorders, fatigue, concentration difficulty, low
motivation (anhedonia)) • several classes of drugs, notably the
antipsychotics, interfere with dopaminergic transmission 13
• The first step in the catecholamine synthesis is the
hydroxylation of the tyrosine and the formation of L-DOPA.
This reaction is catalysed by tyrosine hydroxylase. L-DOPA is
converted into dopamine by the enzyme DOPA decarboxylase.
• • Dopaminergic neurons lack dopamine β- hydroxylase, and
thus do not produce noradrenaline.
Dopamine is broken down into inactive metabolites by: monoamine
oxidase (MAO-A and MAO-B), catechol-O-methyl transferase (COMT) and
aldehyde dehydrogenase (ALDH) acting in sequence -different breakdown
The main product is homovanillic acid (HVA- excreted in the urine) -the
two primary metabolic routes that convert dopamine into HVA are:
Dopamine → DOPAL → DOPAC (4-hydroxyphenylacetic acid) → HVA –
catalyzed by MAO, ALDH, and COMT respectively
Dopamine → 3-Methoxytyramine → HVA – catalyzed by COMT and
After the postsynaptic effects dopamine can be absorbed back into the
presynaptic cell, via reuptake mediated either by the dopamine transporter
or by the plasma membrane monoamine transporter - dopamine can either
be broken down by a monoamine oxidase or repackaged into vesicles by
vesicular monoamine transporter and released again
MAO Synaptic vesicular monoamine
Exists as two isoenzymes, A and B, with an
apparent molecular mass of 60–63 kDa
The two MAO genes,each comprised of 15
exons, are located on the X-chromosome
and appear to have been derived from the
same ancestral gene.
They differ in substrate specificity as well as
selectivity for inhibitors.
MAO-A is more highly expressed in
whereas MAO-B is more abundant in
serotonergic and histaminergic neurons and
in glial cells. Deamination of dopamine
by MAO produces dihydroxyphenylacetic
Determination of the ratio
of DOPAC/dopamine concentrations serves
as a good method for estimating rapid
changes in neuronal activity.
O-Methylation by COMT is primarily
responsible for inactivation of circulating
Consecutive conversion of dopamine
by MAO and COMT yields homovanillic
acid. The enzyme introduces a methyl
group to the catecholamine, which is
donated by S-adenosyl methionine
(SAM). COMT is an intracellular enzyme
located in the postsynaptic neuron. Any
compound having a catechol structure,
like catecholestrogens and catechol-
containing flavonoids, are substrates
Metabotropic G-protein coupled receptors
• D1 – like family: – Includes subtypes D1 and D5
– Activation is coupled to Gs ; activates adenylyl cylcase which leads to increase in concentration
• D2 – like family: – Includes D2 , D3 and D4
– Activation is coupled to Gi ; inhibits adenylyl cyclase leading to decrease in concentration of
– Also open K channels & closes Ca influx
DOPAMINE PATHWAYS & FUNCTION
• 1. Mesostriatal (or nigrostriatal) pathway: 75% of the dopamine in brain,consist of cell bodies in the substantia nigra
whose axon terminate in the corpus straitum,this fibers run in the medial forebrain bundle along with oth
monoamine containing fibres ;this is the pathway that degenerates in Parkinson disease. Involve
coordination of movment
• . 2. Tuberohypophyseal system: is a group of short neurons running from the ventral hypothalamus to the median
eminence and pituitary gland (red arrows). Regulate secretions of prolactin pituitary gland and involved
3. Mesolimbic pathway: The third pathway projects from the ventral
tegmentum to the mesolimbic forebrainespecially the nucleus
accumbens and the amygdaloid nucleus. Associated with
pleasure ,reward and goal directed behavior.
4. Mesocortical pathway: whose cell bodies also lie in the VTA and
which project via the medial forebrain bundle to the frontal
cortex (solid blue arrows).involve motivational and emotional
DOPAMINE RELATED DISEASES
• Parkinson's Disease -When striatum dopamine is depleted to 20% of the original level,
symptoms of Parkinson's Disease appear.
• Treatment: Levodopa, Dopamine Receptor Agonists, Monoamine Oxidase Inhibitors
(MAOIs) Catechol- O- Methyltransferase (COMT) inhibitors, Amantidine
• Schizophrenia-Schizophrenia is thought to be due to an overstimulation of D2 receptors
• chlorpromazine: D2 antagonist, alleviate the symptoms,
• amphetamine: increases D2 stimulation, can induce psychotic symptoms resembling
• Vomiting Dopaminergic neurons can cause nausea and vomiting: all dopamine receptor
agonists (e.g. bromocriptine ) and drugs that increase dopamine release (e.g. levodopa)
cause nausea and vomiting as side effects
• Dopamine antagonists (e.g. phenothiazines , metoclopramide) have antiemetic activity (D2
receptors occur in the area of the medulla (chemoreceptor trigger zone) associated with
• Other motor disorders:
Huntington disease is a progressive brain disorder that causes uncontrolled
movements, emotional problems, and loss of thinking ability (cognition). the most
common form of this disorder, usually appears in a person's thirties or forties
Targeting both DA and glutamate receptor dysfunction could be the best strategy to
treat HD symptoms.
Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both
are neuropsychiatric disorders associated with abnormalities
Cognitive behavioral therapy and Exposure and response prevention
Child and Adolescent Psychiatrist, Neurologist, Psychiatrist, and Paediatrician
Substantial loss of Dopamine
in the striatum (70 – 80%)
Loss of dopamine neurons
in other systems also
and hypothalamic system)
Increasing dopamine levels
nerve grafting with dopamine
containing cells and
deep brain stimulation
Defective dopamine neurotransmission relative excess of
central dopaminergic activity
An increase in DA function in the mesolimbic system and a
decreased function in the mesocortical DA systems(D1
Behaviour similar to the behavioral effects of
ROLE OF DOPAMINE PROLACTIN SECRETION
Inhibits secretion of prolactin by acting on D2
Treatment of hyperprolactinemia
Ergot derivatives : bromocriptine, cabergoline, pergolide.
Non ergot : QuinagolideCabergoline – 0.25(max 1) mg orally twice a week
Quinagolide – 0.2 -0.6 mg orally per day longer t1/2 , better
toleratted than ergot derivative
Bromocriptine 2.5 mg OD/BD upto 15 days
ROLE OF DOPAMINE IN RENAL SYSTEM
At low dose (0.5 to 3 micg /kg /min ):- Selectively activates
dopamine specific receptors in the renal and splanchnic
Increase blood flow in these region.
Increase in urinary Na excretion
HEART AND VASCULATURE
At low concentrations, circulating DA primarily stimulates
vascular D1 receptors, causing vasodilation and reducing cardiac
DA is able to activate adrenergic receptors to further increase
The net result is a decrease in blood pressure and an increase in
Goodman and Gilman’s The Pharmacological Basis of Therapeutics 12th edi; chap
Bertram Katzung ; Basic and clinical pharmacology ; Drug ofabuse ;553-568 ;12th
HL Sharma and KK;Antipsychotics ;2ndedition;chap 33; 532-542.
Rang H.P.and Dale M.M;Antipsychotics;7th edition; 39,45,49; 557
• Histamine is hydrophilic molecule consisting of an imidazole ring
• Histamine is involved in inflammatory and anaphylactic
• Sinus problems, hay fever, bronchial asthma, hives, eczema,
contact dermatitis, food allergies and reactions to drugs are
all allergic reactions associated with the release of histamine
and other autocoids, such as serotonin, leukotrienes, and
• Almost all mammalian tissues contain histamine
• Widely distributed in skin, GIT mucosa, lungs, brain, CSF and
• It is also a component of some venoms, sting secretion,
bacteria and plants
• The mast cell is the predominant storage site for histamine in
• The concentration of histamine is particularly high in tissues
that contain large numbers of mast cells, such as skin, bronchial
tree mucosa, and intestinal mucosa.
HISTAMINE PATHWAY IN BRAIN
All of the neurons that are synthesizing
histamine are present in a part of the brain
called the tuberomammillarynucleus; that is actually
a part of the hypothalamus.
There are only about 64,000 of these
neurons in the brain.
These neurons innervate the cortex, the
pituitary, the thalamic nuclei, the amygdala,
hippocampus, spinal cord, and the
Histamine activates neurons by stimulating
specific receptors that have been molecularly
What that means is that molecular biologists
have identified the DNA sequence that codes
for the proteins.
SYNTHESIS STORAGE AND RELEASE
• Formed by the decarboxylation of the amino acid
histidine by the enzyme L-histidine decarboxylase
• The chief site of histamine storage in most tissues is the
mast cell; in the blood, it is the basophil.
• Metabolised to N-methylhistamine by histamine-
Nmethyltransferase and Imidazoleacetic acid by the
nonspecific enzyme diamine oxidase (DAO)
• These metabolites have little or no activity and are
excreted in the urine.
Mechanism of antigen-antibody reaction induced release
of histamine from mast cell
In sensitized atopic individual, specific reaginic (IgE) antibody is
produced and gets bound to Fc epsilon receptor I (FcεRI) on the
surface of mast cells. On challenge, the antigen bridges IgE
molecules resulting in transmembrane activation of a tyrosine-
protein kinase (t-Pr-K) which phosphorylates and activates
phospholipaseCγ. Phosphatidyl inositol bisphosphate (PIP2) is
hydrolysed and inositol trisphosphate (IP3) is generated which
triggers intracellular release of Ca2+. The Ca2+ ions induce fusion
of granule membrane with plasma membrane of the mast cell
resulting in exocytotic release of granule contents. In the granule,
positively charged histamine (Hist+) is held complexed with
negatively charged protein (Prot–) and heparin (Hep–) molecules.
Cationic exchange with extracellular Na+ (and Ca2+) sets
histamine free to act on the target cells.
1 IMMUNOLOGICAL RELEASE
• Histamine is released from mast cells by
exocytosis during inflammatory or
• Cell fixed IgE antibodies interact with
• Mast cells if sensitized by surface IgE
antibodies,degranulate and rapidly
relese many active compounds
including histamine when exposed to
• THE IMMEDIATE ALLERGIC REATION
2 NON IMMNUNE MECHANISM :MECHANICAL OR
ANY PHYSICAL OR CHEMICAL AGENT THAT INJURIES TISSUE
SKIN ,MUCOSA ARE SENSITIVE TO INJURY AND WIL CAUSE
IMMEDIATE RELEASE OF HISTAMINE FROM MAST CELLS .
3 DRUGS OR OTHER FORGEIN COMPUNDS:
POLYMERS LIKE DEXTRAN, POLYVINYL PYRROLIDONE (PVP).
SOME BASIC DRUGS—TUBOCURARINE, MORPHINE,
ATROPINE, PENTAMIDINE, POLYMYXIN B, VANCOMYCIN
AND EVEN SOME ANTIHISTAMINICS DIRECTLY RELEASE
HISTAMINE WITHOUT AN IMMUNOLOGICAL REACTION.
SURFACE ACTING AGENTS LIKE TWEEN 80, COMPOUND
48/80 ETC. THE PRIMARY ACTION OF THESE SUBSTANCES IS
RELEASE OF HISTAMINE FROM MAST CELLS, THEREFORE
THEY ARE CALLED ‘HISTAMINE LIBERATORS’
RELEASE AND FUNCTION
IT IS RELEASED FROM STORAGE GRANULES AS A RESULT OF
THE INTERACTION OF ANTIGEN WITH IMMUNOGLOBULIN E
ANTIBODIES ON THE MAST CELL SURFACE
• HISTAMINE PLAYS A CENTRAL ROLE IN IMMEDIATE
HYPERSENSITIVITY AND ALLERGIC RESPONSES.
• THE ACTIONS OF HISTAMINE ON BRONCHIAL SMOOTH
AND BLOOD VESSELS ACCOUNT FOR MANY OF THE SYMPTOMS
OF THE ALLERGIC RESPONSE
. • IN ADDITION, CERTAIN CLINICALLY USEFUL DRUGS CAN ACT
DIRECTLY ON MAST CELLS TO RELEASE HISTAMINE, THEREBY
EXPLAINING SOME OF THEIR UNTOWARD EFFECTS.
• HISTAMINE HAS A MA JOR ROLE IN THE REGULATION OF
GASTRIC ACID SECRETION AND ALSO MODULATES
Histamine acts on three types of receptor,all of
which are Gprotein coupled receptor and occur in
most brain regions.
H1 receptor are mainly located at the
postsynaptically and cause excitation
H2 and H3 receptors are inhibitory ,respectivly post
H3 receptor being inhibitory “AUTORECEPTOR”on
histamine relesing neurons.
MECHANISM OF ACTION
HISTAMINE MEDITATES ITS EFFECT BY INTERACTING WITH
PROTEIN COUPLED HISTAMINE RECEPTORS H1,H2,H3 AND
Enzyme :phoospholipase C and
protein kinase C
cyclase C and
protein kinase A
Histamine has dominant physiological role in mediating
secretion of HCl in the stomach
Nonmast cell histamine occurs in gastric mucosa, possibly in
cells called ‘histaminocytes’ situated close to the parietal cells.
This histamine has high turnover rate. It is released locally under
the influence of all stimuli that evoke gastric secretion (feeding,
vagal stimulation, cholinergic drugs and gastrin) and activates
the proton pump (H+K+ ATPase) through H2 receptors. H2
blockers not only suppress acid secretion induced by histamine
but also markedly diminish that in response to ACh and gastrin
Mediation of hypersensitivity reactions was the first role
ascribed to histamine. It is an important, but only one of the
mediators of such phenomena. Released from mast cells
following AG : AB reaction on their surface (involving IgE type
of reaginic antibodies;) in immediate type of hypersensitivity
reactions, histamine is causative in urticaria, angioedema,
bronchoconstriction and anaphylactic shock.
Histamine is believed to be the afferent transmitter
which initiates the sensation of itch and pain at
sensory nerve endings.
Nonmast cell histamine occurs in brain, especially
hypothalamus and midbrain.
It is involved in maintaining wakefulness; H1
antihistaminics owe their sedative action to blockade
of this function.
In the brain H1 agonism suppresses appetite
Histamine also appears to participate as a transmitter regulating
body temperature, cardiovascular function, thirst,
Histamine is a mediator of vasodilatation and other
changes that occur during inflammation.
Tissue growth and repair
Because growing and regenerating tissues contain high
concentrations of histamine, it has been suggested to play
an essential role in the process of growth and repair.
Histamine receptors are GPCRs
• H1 receptors: mediate effects on smooth muscle leading to
vasodilatation, increased vascular permeability, and contraction of
nonvascular smooth muscle.
• H2 receptors: mediate histamine stimulation of gastric acid
secretion and may be involved in cardiac stimulation.
• H3 receptors: feedback inhibitors in CNS, gastrointestinal tract,
Histamine causes marked dilatation of smaller blood vessels,
including arterioles, capillaries and venules. On s.c. injection
Larger arteries and veins are constricted by histamine:
mediated by H1 receptor on vascular smooth muscle.
Histamine also causes increased capillary permeability due to
separation of endothelial cells → exudation of plasma. This is
primarily a H1 response.
Injected intradermally, it elicits the triple response consisting of:
Red spot: due to intense capillary dilatation. Wheal: due to
exudation of fluid from capillaries and venules. Flare: i.e.
redness in the surrounding area due to arteriolar dilatation
mediated by axon reflex.
Direct effects of histamine on in situ heart are not prominent, but the
isolated heart, especially of guinea pig, is stimulated—rate as well as force
of contraction is increased. These are primarily H2 responses but a H1
mediated negative dromotropic (slowing of A-V conduction) effect has also
Histamine causes marked increase in gastric secretion—primarily of acid
but also of pepsin .This is a direct action exerted on parietal cells through
H2 receptors and is mediated by increased cAMP generation, which in turn
activates the membrane proton pump (H+ K+ ATPase). Histamine can
increase other secretions also, but the effect is hardly discernable
. Sensory nerve endings
occurs when histamine is injected i.v. or intracutaneously. Higher
concentrations injected more deeply cause pain. These are reflections of
the capacity of histamine to stimulate nerve endings.
Histamine does not penetrate bloodbrain barrier—no central effects are
seen on i.v. injection. However, intracerebroventricular administration
produces rise in BP, cardiac stimulation, behavioural arousal,
hypothermia, vomiting and ADH release. These effects are mediated
through both H1 and H2 receptors.
a. Triple effect on terminal vasculature (itching & pain): – reddening
at injection site due to vasodilation – wheal or disk of edema within
1 to 2 min – a large, bright crimson flare or halo surrounding the
wheal b. IV Histamine: fall in blood pressure, cutaneous flushing,
over the face and upper trunk, rise in skin temperature, intense
2. Smooth muscle of bronchioles; contraction of nonvascular
3. Exocrine glands: potent stimulation of gastric secretion (HCl &
pepsin), salivary and lacrimal gland secretion, catecholamines
4. Peripheral Nervous system: itching and pain
Histamine clinical use Practical applications of histamine are
limited to uses as a diagnostic agent.
Histamine (histamine phosphate) is used to assess
nonspecific bronchial hyperreactivity in asthmatics and as a
positive control injection during allergy skin testing
• When histamine level is too high ,histamine intolerance occures
• Symptoms:headache,high BP,anxiety,dizzeness,irregular heart rate
• Why it occurs?
• Enzyme diamine oxidase is responsible for the breakdown of histmaine.
• If there is a deficency of diamine oxidase this intolerance occures
H1-antihistamines are clinically used in the treatment of histamine-mediated allergic
conditions. These indications may include
•Allergic dermatological conditions (contact dermatitis)
•Rhinorrhea (Runny nose)
•Pruritus (atopic dermatitis, insect bites)
•Anaphylactic or anaphylactoid reactions—adjunct only
•Nausea and vomiting
•Sedation (first-generation H1-antihistamine
Other common adverse effects in first-generation H1-antihistamines include dizziness, tinnitus,
blurred vision, euphoria, uncoordination, anxiety, increased appetite leading to weight
gain, insomnia, tremor, nausea and vomiting, constipation, diarrhea, dry mouth, and dry cough.
Infrequent adverse effects include urinary
retention, palpitations, hypotension, headache, hallucination, and psychosis.
• Second generation advantages
• No anticolinergic side effect
• Minimum sedation as donot cross BBB
• Absorption: Antihistaminics (H1 receptor antagonists)
are well absorbed from oral and parenteral routes
• Distribution: widely in the body and enter brain.
Newer compounds penetrate the brain poorly.
• Metabolism: In liver
• Excretion: In urine
•Famotidine (Pepcid AC, Pepcid Oral)
•Cimetidine (Tagamet, Tagamet HB)
•Ranitidine (Zantac, Zantac 75, Zantac Efferdose, Zantac injection, and
•Nizatidine Capsules (Axid AR, Axid Capsules, Nizatidine Capsules)
H2 BLOCKERS• H2 blocker is use in peptic ulcer ,gastroeshophagal reflux disease ,dyspepsiea
Side effects from H2 blockers are rare.
•Famotidine. The most common side effect is headache.
•Cimetidine. Side effects are rare. But diarrhea, dizziness,
rashes, headaches, and gynecomastia may occur.
•Ranitidine. The most common side effect is headache.
•Nizatidine. Side effects are rare.
In humans 10% of serotonin (5-hydroxytryptamine, or 5HT) occurs
primarily in the platelets and brain.
• Serotonin was the name given to the vasoconstrictor
substance which appeared in the serum when blood
clotted and Enteramine to the smooth muscle contracting
substance present in enterochromaffin cells of gut mucosa
SEROTONIN SYNTHESIS STORAGE AND RELEASE
• Tryptophan is initially hydroxylated to form 5-hydroxytryptophan,
decarboxylation of the latter compound results in the formation
• Serotonin is initially oxidatively deaminated to form 5-
hydroxyindoleacetaldehyde, and rapidly oxidized to the major metabolite 5-
hydroxyindoleacetic acid and excreted in the urine
Serotoninpathways-the most of the serotonin in the
in the brainstem,specifically in the raphe nuclei
These neurons control muscle activity considerable
amounts are present in areas of the hypothalamus,
the limbic system
Regulate memory and mood in frontal cortex -
regulate cognition and memory and the pituitary
Seven families of 5-HT receptors
(5-HT1 , 5-HT2 , 5-HT3 , 5-HT4, 5-HT5 , 5-HT6 , 5-HT7
All 5-HT receptors are G protein coupled receptors, except 5-
HT3 which is a Ligand gated ion channel, its activation elicits
5-HT1 : decreasing cAMP production
5-HT2 : produce IP3/DAG 5-HT4,7 : increasing cAMP
Occur mainly in the brain The 5-HT1A subtype is particularly
important in the brain, in relation to mood and behaviour. The 5-HT1D
subtype, which is expressed in cerebral blood vessels, is important in
migraine and is the target for Sumatriptan
Particularly important in the periphery Stimulate IP3 /DAG formation
The 5-HT2A subtype is functionally the most important, mediates
smooth muscle contraction and platelet aggregation
Occur mainly in the PNS, particularly on nociceptive sensory
neurons and autonomic and enteric neurons, 5-HT3 receptors
also occur in the brain, particularly in the area postrema, a region
of the medulla involved in the vomiting reflex
Occur in the brain, as well as in peripheral organs such as the
GIT, bladder and heart. Their main physiological role appears to
be in the GIT where they produce neuronal excitation and
mediate the effect of 5-HT in stimulating peristalsis
Two genes have been identified that give rise to 5-ht5a and 5-
ht5b proteins with structures consistent with GPCRs although in
humans the 5-ht5b gene is a pseudogene since a stop codon has
evolved that would, if expressed, result in a truncated protein devoid of
key functional moieties of the receptor. The predicted protein
sequences display less than 38% amino acid sequence identity to other
5-HT GPCRs, thus clearly distinguishing the 5-ht5a protein from other
The 5-HT6 receptor is a GPCR that couples via Gs to increase cAMP producti
although additional transduction pathways have been proposed. The recepto
structurally differentiated from the other 5-HT receptors with less than 34%
acid sequence identity.
The 5-HT7 receptor is a GPCR that couples via Gs to increase cAMP
production with some other transduction pathways also implicated in
receptor function (e.g. ERK, Galpha12/RhoA/Cdc42). The structure displays
less than 39% amino acid sequence identity to other 5-HT receptors.
Several splice variants have been described.
• Serotonin syndrome occurs when you take medications that cause high
levels of the chemical serotonin to accumulate in your body. Signs and
• Agitation or restlessness,Confusion,Rapid heart rate and high blood
pressure,Dilated pupils,Loss of muscle coordination ,Muscle
rigidity,Heavy sweating,Diarrhea,Headache,Shivering,Goose bumps
These drugs and supplements include:
Selective serotonin reuptake inhibitors (SSRIs), antidepressants such
as citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine,
paroxetine (Paxil) and sertraline (Zoloft)
Serotonin and norepinephrine reuptake inhibitors
(SNRIs), antidepressants such as trazodone, duloxetine (Cymbalta) and
Bupropion (Wellbutrin, Zyban), an antidepressant and tobacco-
Tricyclic antidepressants, such as amitriptyline and nortriptyline
Monoamine oxidase inhibitors (MAOIs), antidepressants such as
isocarboxazid (Marplan) and phenelzine (Nardil)
Anti-migraine medications such as triptans (Axert, Amerge, Imitrex),
carbamazepine (Tegretol) and valproic acid (Depakene)
Pain medications such as opioid pain medications including codeine
(Tylenol with codeine), fentanyl (Duragesic), hydrocodone meperidine
(Demerol), oxycodone (Oxycontin, Percocet, Percodan) and tramadol
Lithium (Lithobid), a mood stabilizer
Illicit drugs, including LSD, Ecstasy, cocaine and amphetamines
Herbal supplements, including St. John's wort, ginseng and nutmeg
Over-the-counter cough and cold medications containing
dextromethorphan (Delsym, Mucinex DM, others)
Anti-nausea medications such as granisetron, metoclopramide
(Reglan), droperidol (Inapsine) and ondansetron (Zofran)
Linezolid (Zyvox), an antibiotic
Ritonavir (Norvir), an anti-retroviral medication used to treat
OBSESSIVE COMPLUSIVE DISORDER
• It is an anxiety disorder chareterised by unresonable thoughts and fear.
• Level of serotonin is reduced.
• Depression is the most common of all affective disoreders(disoreder of
mood,disturbuance of thoughts)ranges from mild to severe.
• Depression is cause by deficit of monoamine transmitter in certain areas
5 HT AGONIST
Selective 5-HT1A agonists
: 8-hydroxy-2-(di-npropylamino) tetralin (8-OH DPAT) highly selective
agonist but not used clinically Buspirone, Gepirone, Ipasapirone : potent 5-
HT1A agonists used in treating anxiety.
Given orally at a dosage of 15 mg/day the drug is rapidly absorbed half-
life of about 2.5 hours
The mean peak plasma concentration (Cmax) is approximately 2.5 μg/L,
and the time to reach the peak is under 1 hour, however it takes days or
weeks to produce its effect. The absolute bioavailability of buspirone is
Side effects: Mainly nausea, dizziness, headache, restlessness but no
sedation or loss of coordination
Sumatriptan, used for treating migraine Pharmacokinetics:
Administered subcutaneously, orally, and intranasally. Orally, single
dose of 25, 50, or 100 mg, if patient has a partial response to the
initial dose, a single additional dose may be taken after 2 h up to a
max of 200 mg/day Subcutaneous 6 mg initially. May repeat once
after 1 h (max, 6 mg
5-HT4 receptor agonists
Metoclopramide which stimulate coordinated peristaltic activity
(prokinetic action), are used for treating gastrointestinal
disorders, increase motility Pharmacokinetics: Given orally at a
dose of 5-10 mg, is rapidly and well absorbed, bioavailability is
80% ± 15.5%, plasma half life or 4-5 h and peak plasma
Side effects :
Fatigue, motor restlessness, spasmodic torticollis, occulogyric crisis,
also can cause galactorrhoea and disorders of menstruation.
Contraindications : Metoclopramide should not be used whenever
stimulation of gastrointestinal motility might be dangerous, e.g., in
the presence of gastrointestinal hemorrhage, mechanical
obstruction, or perforation
5-HT2 RECEPTOR ANTAGONISTS :
CYPROHEPTADINE: PRIMARILY BLOCKS 5-HT2A RECEPTOR,
USED IN CONTROLLING THE SYMPTOMS OF CARCINOID
TUMORS. METHYSERGIDE & DIHYDROERGOTAMINE: USED
MAINLY FOR MIGRAINE PROPHYLAXIS. KETANSERIN: 5HT2
(BLOCKADE OF 5HT2A IS STRONGER THAN OF 5HT2C) AND Α1
ANTAGONIST, USED AS ANTIHYPERTENSIVE. CLOZAPINE:
PARTIAL ANTAGONIST AT 5-HT2A/2C RECEPTOR, RISPERIDONE:
IS A COMBINED 5-HT2A + DOPAMINE D2 ANTAGONIST
: Clozapine is usually used only in patients that have not responded to
other anti-psychotic treatments due to its danger of causing
Common side effects include extreme constipation, nighttime drooling,
muscle stiffness, sedation, tremors, hyperglycemia, and weight gain
. The risk of developing extrapyramidal symptoms such as tardive
dyskinesia is below that of typical antipsychotics
HT3 receptor antagonists :
Ondansetron, Granisetron, Tropisetron:
These agents have an important place in treating emesis linked with
chemotherapy. Long duration of action.
Can be administered as a single dose prior to chemotherapy.
Are extensively metabolized in the liver.
Elimination is through the urine.
Common side effect is headache.
5-HT mixed agonist and antagonist : Lysergic acid diethylamide
(LSD) Is a potent hallucinogen, activates 5-HT1A, 5-HT2A/2C, 5-HT5-7,
also antagonizes 5-HT2A receptors in the ileum.
• Other related drugs : SSRI : specifically inhibit serotonin reuptake, have
300-3000 fold selectivity, drug of choice in treating depression. Example :
Fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline, Indication :
Depression, obsessive compulsive disorder, panic disorder, generalized
anxiety and bulimia nervosa.
Pharmacokinetics : All the SSRIs are well absorbed after oral
administration. All have large volume of distribution. Plasma half
lives range between 16-36 h but Fluoxetine have a half life of 50 h.
Fluoxetine and paroxetine are inhibitors of enzyme CYP2D6.
Excretion is primarily through the kidneys, except Paroxetine and
Sertraline undergo 35% fecal excretion, 50% renal excretion.
Dosage should be adjusted downward in hepatic impairment
Adverse effects : Nausea, vomiting,
diarrhea, Headache, restlessness, fatigue,
sleep disturbances. Should be used
cautiously in children and teenagers, 1 out
of 50 children become suicidal as a result of