Biogenic amine Neurotransmitters- Acetylecholine, Norepinephrine, Histamine.

1. Dr. Rujul Modi
PART-2

2. NOREPINEPHRINE & EPINEPHRINE
ACETYLCHOLINE
HISTAMINE
02
CONTENTS

3.  Neurotransmitters are chemical signals released from
presynaptic nerve terminals into the synaptic cleft.
 The subsequent binding of neurotransmitters to specific
receptors on postsynaptic neurons (or other classes of
target cells) transiently changes the electrical properties of
the target cells, leading to an enormous variety of
postsynaptic effects.
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DEFINITION

4. 1. Molecule is synthesized in neuron
2. Molecule is present in presynaptic neuron & is released on
depolarisation in physiologically significant amount
3. When administered exogenously as a drug, the exogenous
molecule mimics the effect of endogenous neurotransmitter
4. A mechanism in neurons or synaptic cleft acts to remove or
deactivate the neurotransmitter
CRITERIA FOR NEUROTRANSMITTERS
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5. • Norepinephrine is the more important and more abundant of the
two related neurotransmitters in the brain, although adrenally
derived epinephrine is more abundant than norepinephrine in
the serum.
• Locus coeruleus (LC) is the origin of most norepinephrine in the
brain followed by the lateral tegmental area .
• Levels of epinephrine in the CNS are only about 10% of the levels
of norepinephrine
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NOREPINEPHRINE & EPINEPHRINE

6. • Norepinephrine, as with other Catecholamines, itself cannot
cross the bloodbrain barrier
• The major concentration of noradrenergic (and adrenergic) cell
bodies that project upward in the brain is in the compact locus
coeruleus (LC) in the Pons.
• The axons of these neurons project through the medial forebrain
bundle to the cerebral cortex, the limbic system, the thalamus,
and the hypothalamus
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PATHWAY

7. 07
LC neurons
primarily
targeting the
 Forebrain,
 Thalamus,
 Cerebellum &
 Spinal cord.

8.  Locus coeruleus-norepinephrine neurons exhibit, Tonic firing with
short period of burst firing.
 Alteration in the tonic mode are associated with Sleep-wake cycle.
 LC norepinephrine neurons have important role in vigilance,
attention and working memory.
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9. Dopamine
Dopamine Beta-
Hydroxylase (DBH)
Norepinephrine
PNMT
Phenol-N-methyl transferase
Epinephrine
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SYNTHESIS

10. Site of Action
of
Drugs

11. Site -2 : NE is taken up from cytoplasm and transported into storage
vesicles by VMAT-2.
 Reserpine inhibits VMAT and deplets NE stores, previously was
widely used as an antihypertensive.
 Tetrabenazine also interferes with the uptake-storage mechanism
and has been used for treatment of hyperkinetic movement d/o.
Site-3,4,5 : After release NE can interact with two categories of
receptors - α1 , α2 and β-receptors. Majority of adrenergic receptors
are localized postsynaptically where they mediate cellular response.
 Propranolol is an antagonist of β-receptor and is used to treat
performance anxiety and HTN.

12.  Prazosin (used as an antihypertensive) has anxiolytic effects also
and used in the treatment of PTSD
Site-6 : α2 NE autoreceptors modulate synthesis and release of NE
and also modulate impulse flow.
 Clonidine is α2 agonist and is used to treat acute phase of opioid
withdrawal, and Tourette syndrome (also Guanfacine)
 Lofexidine , a structural analogue of clonidine, may be safer, as it
has similar withdrawal suppressing effect but causes little
hypotension and sedation than clonidine*.
*( Washton AM, Resnik RB. Clonidine in opiate withdrwal:review and appraisal of clinical findings.
Pharmacotherapy. 1981;1(2):140-146.doi:10.1002/j.1875-9114.1981.tb03561.x )
 Yohimbine is an antagonist of α2
Washton AM, Resnick RB. Clonidine in opiate withdrawal: review and appraisal of clinical findings. Pharmacotherapy. 19

13. Site-7 : The synaptic action of NE is terminated by its reuptake
through Norepinephrine plasma membrane Transportes (NET)
 The TCA, such as Desipramine inhibits these uptake mechanism.
 Newer Antidepressants like Atomoxetine , Duloxetine and
Venlafaxine (SNRIs) are more selective for NET.
*Duloxetine is approved for fibromyalgia and chronic pain syndrome.
 Trazadone, Nefazodone (SARI-Serotonin antagonist and reuptake
inhibitors) have combined actions :
5HT2A 5HT2C antagonist +
SNDRI (serotonin-norepinephrine-dopamine reuptake inhibitor)
S/E = Priapism (unwanted-persistant erection)

14. Bupropion ( NDRI- norepinephrine-dopamine reuptake inhibitor ) is
FDA approved for smoking cessation and adult depression.
Also it is used for Hypoactive sexual desire disorders (HSDD) in
women and Adult ADHD( Off-label, not approved by US-FDA)
Bremelanotide is recently (21st june,2019)* approved by FDA for HSDD
in premenopausal women and is given by SC route.
*Ref : Goldstein I et al. (2017) “Hypoactive Sexual Desire Disorder: International Society for the Study of Women’s Sexual Health
(ISSWSH) Expert Consensus Panel Review” Mayo Clin Proc.; 92(1):114-128

15. Site-8 : NE is metabolized by MAO and is preferential substrate for
MAO-A.
 MAO-A inhibitors blocks these metabolism of NE and contribute to
their antidepressant property.
Ex:
Irreversible = Isocarboxazid , Phenelzine, Tranylcypromine
Reversible = Moclobemide
Site-9 : NE is also metabolized by COMT ,which is inhibited by
Tolcapone and Entacapone(used in parkinsons disease).

16. α-adrenergic receptors & β-adrenergic receptors. Subtyped into
 Three types of α1-receptors (α1A, α1B, and α1D),
 Four types of α2-receptors (α2A, α2B, α2C, α2D), and
 Three types of β-receptors (β1, β2, and β3).
α -receptors inhibit formation of cAMP (Gi), and β -receptors stimulate
formation of cAMP. (Gs)
α1 and β-receptors located postsynaptically, whereas α2 exist both pre- and
post synaptically.
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ADRENERGIC RECEPTORS

17. 17
ACETYLCHOLINE
SYNTHESIS

18. Central Cholinergic Projections
 Basal forebrain :- includes
Nucleus basalis (of Meynert), Medial
septal nuclei & Diagonal band of Broca
 Cholinergic interneurons :- located in
pedunculopontine nucleus (PPT) & in
Laterodorsal pontine tegmentum (LDT)
o Innervates the thalamus & midbrain
regions.
They are the principle source of Striatal
Ach.

19.  Central cholinergic neurons are involved cognition, learning and
memory, arousal, & motor control.
 In Alzeimer 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.
• Drugs that increase cholinergic activity by blocking it’s breakdown
by acetyl cholinesterase (e.g., Donepezil ) have been shown to be
effective in the treatment of dementia of the Alzheimer's type

20.  Cholinergic neurons may continue to fire during REM sleep and
have been proposed to play a role in REM sleep induction
 The modulation of striatal cholinergic transmission has been
implicated in the anti parkinsonian actions of anticholinergic
agents.
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21. 1. G-protein-coupled muscarinic receptors and
2. Nicotinic ligand-gated ion channels
• Central muscarinic receptors have been implicated in
- learning and memory
- sleep regulation
- pain perception, motor control, and
- the regulation of seizure susceptibility
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CHOLINERGIC RECEPTORS

22. Five Subtypes of muscarinic receptors :
M1
• M1 receptors are the most abundantly expressed muscarinic
receptors in the forebrain, including the cortex, hippocampus, and
striatum.
• Pharmacological evidence has suggested their involvement in
memory and synaptic plasticity
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MUSCARINIC RECEPTORS

23. M2
In addition to heart, where they function to lower heart rate, M2
receptors are widely distributed throughout the brain.
M2 receptors appear to mediate tremor , hypothermia, and analgesia
induced by muscarinic agonists
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MUSCARINIC RECEPTORS

24. M3
• Found in smooth muscles and salivary glands.
Play a major role in smooth muscle contraction in the GI & GU tracts
and to mediate salivation
• Although M3 receptors are found at modest densities in many
areas of the CNS, no central role has been elucidated
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MUSCARINIC RECEPTORS

25. M4 receptors
Expressed in the hippocampus, cortex, striatum, thalamus, and
cerebellum
M5 receptors are expressed in various peripheral and cerebral
blood vessels and comprise a very small percentage of muscarinic
receptors in the brain
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MUSCARINIC RECEPTORS

26. • Nicotinic acetylcholine receptors, (like 5HT3 receptors) are
members of the ligand gated ion channel superfamily.
• In the periphery, nicotinic Ach receptors are found in skeletal
muscle, autonomic ganglia, and the adrenal medulla
• In the brain, they are found in many locations including the
neocortex, hippocampus, thalamus, striatum, hypothalamus,
cerebellum, substantia nigra, ventral tegmental area, and dorsal
raphe nucleus
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NICOTINIC RECEPTORS

27. • They frequently appear to mediate presynaptic enhancement of
neurotransmitter release, influencing the release of acetylcholine,
dopamine, norepinephrine, serotonin, as well as GABA and
glutamate
• Nicotinic receptors have been implicated in cognitive function,
especially working memory, attention, and processing speed
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NICOTINIC RECEPTORS

28. • Cortical and hippocampal nicotinic Ach. receptors appear to be
significantly decreased in Alzheimer's disease, and nicotine
administration improves attention deficits in some patients
• The acetyl cholinesterase inhibitor Galantamine used in the
treatment of Alzheimer's disease also acts to positively modulate
nicotinic receptor function.
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NICOTINIC RECEPTORS

29. • The reinforcing properties of tobacco use are proposed to involve
the stimulation of nicotinic acetylcholine receptors located in
mesolimbic dopaminergic reward pathways
• Varenicline (Chantix) is a partial agonist with selectivity at the
α4/β2 nicotinic receptors is widely used as an aid in cessation of
smoking.
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NICOTINIC RECEPTORS

30. • The most common use of anticholinergic drugs in psychiatry is in
treatment of the motor abnormalities caused by the use of classic
antipsychotic drugs (e.g., haloperidol).
• The efficacy of the drugs for that indication is determined by the
balance between acetylcholine activity and dopamine activity in
the basal ganglia.
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NICOTINIC RECEPTORS

31. • In healthy people, the activity of the nigrostriatal dopamine
pathway is partially balanced by the activity of cholinergic
pathways in the basal ganglia.
• Blockade of D2 receptors in the striatum upsets this balance, but
the balance can be partially restored, at a lower set point, by
antagonism of muscarinic receptors
• Excessive blockade of CNS cholinergic receptors causes confusion
and delirium.
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NICOTINIC RECEPTORS

32. • Mutation in one of the Nicotinic receptor subunit genes is
responsible for specific form of Epilepsy known as -
Autosomal dominant frontal lobe epilepsy (ADNFLE)
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NICOTINIC RECEPTORS

33. Histaminergic cell bodies
• The posterior hypothalamus termed the tuberomammillary
nucleus
- project diffusely throughout brain and spinal cord
Ventral ascending projections :
Course through the medial forebrain bundle and then innervate the
hypothalamus, diagonal band, septum, and olfactory bulb.
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HISTAMINE

34.  Dorsal ascending projections
Innervate the thalamus, hippocampus, amygdala, and
Rostral forebrain
 Descending projections
Travel through the midbrain central gray to the dorsal hindbrain
and spinal cord.
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35. • The hypothalamus receives the densest histaminergic innervation,
consistent with a role for this transmitter in the regulation of
autonomic and neuroendocrine processes.
• Histamine is distributed throughout most tissues of the body,
predominantly in mast cells.
• The number of histaminergic neurons in human is about 64000*
* Baronio D, Gonchoroski, T.,Castro,K. et al. Histaminergic system in brain disorders: lessons from the translational
approach and future perspectives. Ann Gen Psychiatry 13,34(2014) doi:10.1186/s12991-014-0034-y
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36. Histaminergic systems have been proposed to modulate
- Arousal,
- Wakefulness,
- Feeding behaviour, and
- Neuroendocrine responsiveness
Four histaminergic receptor subtypes : H1, H2, H3, and H4
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HISTAMINE RECEPTORS

37. H1 receptors are expressed throughout the body, particularly in
smooth muscle of the gastrointestinal tract and bronchial walls as
well as on vascular endothelial cells.
• H1 receptors are widely distributed within the CNS, with
particularly high levels in the thalamus, cortex, and cerebellum.
• Antipsychotics induced weight gain is due to their antagonistic
action on H1 & 5HT2C receptors
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HISTAMINE RECEPTORS

38.  AIWG is highest with Olanzapine and clozapine. And least with
Aripiprazole
 Recent studies revealed that, the use of Reboxetine (SNRI) along
with Olanzapine, helps to minimize the weight gain.*
Ref : Dayabandara M, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera C, de Silva VA. “Antipsychotic-
associated weight gain:management strategies and impact on treatment adherence.” Neuropsychiatric disease and
treatment vol.13 2231-2241. 22 Aug.2017,doi:10.2147/NDT.S113099
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HISTAMINE RECEPTORS

39. H2 receptors
• Widely distributed throughout the body and are found in gastric
mucosa, smooth muscle, cardiac muscle, and cells of the immune
system.
• Within the CNS, H2 receptors are abundantly expressed in the
neocortex, hippocampus, amygdala, and striatum.
• H2 receptor antagonists are widely used in the treatment of peptic
ulcer disease.
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HISTAMINE RECEPTORS

40. H3 receptors
• Located presynaptically on axon terminals
• Particularly high levels of H3 receptor binding are found in the
frontal cortex, striatum, amygdaloid complex, and substantia nigra
• Antagonists of H3 receptors have been proposed to have appetite
suppressant, arousing, and cognitive-enhancing properties.
H4 receptor : Detected predominantly in the spleen, bone marrow,
and leukocytes
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HISTAMINE RECEPTORS

41.  Postmortem studies have revealed that brain histamine levels are
decreased in Alzheimer’s disease patients whereas abnormally
high levels found in brain of Schizophrenic patients.*
 Low histamine levels are are associated with convulsions.
* (Nuutinen S, Panula P. Histamine in neurotransmission and brain diseases. Adv Exp Med Biol. 2010;709:95-
107.doi:10.1007/978-1-4419-8056-4_10)
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HISTAMINE RECEPTORS

42. 1. KAPLAN AND SADDOCK’S COMPREHENSIVE TEXTBOOK OF PSYCHIATRY. 10th ed.
2. STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY: NEUROSCIENTIFIC BASIS AND PRACTICAL APPLICATIONS.
3. KAPLAN & SADDOCKS SYNOPSIS OF PSYCHIATRY 10th ed.
4. GUYTON & HALL PHYSIOLOGY.
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REFERENCES

43. THANK YOU
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