Norepinephrine, a critical neurotransmitter and hormone, is synthesized from tyrosine and plays roles in the central nervous system (CNS) and stress responses. Its regulation involves transporters and enzymes, with therapeutic implications for mental health conditions through drugs that affect norepinephrine reuptake. The neurotransmitter is linked to several conditions like anxiety, ADHD, and PTSD, and is influenced by other monoamines such as serotonin.

1. NOREPINEPHRINE
Presented by Dr. Amrutha G
Moderator Dr. V Sree Chaitanya
Chairperson Dr. T V Pavan Kumar

2. Introduction
Norepinephrine also called noradrenaline is an important biogenic neurotransmitter in the CNS.
Acts as a hormone outside the CNS (produced by the neuroendocrine chromaffin cells of the adrenal
medulla & released into bloodstream)
Structurally, it is a phenylethylamine.
Norepinephrine release is lowest during sleep, rises during wakefulness,
and reaches much higher levels during situations of stress or danger
‘’ fight-or-flight response’’.

3. Synthesis
The Catecholamines - Epinephrine, Norepinephrine and
Dopamine share a common synthetic pathway.
Precursor – Tyrosine
 Tyrosine (TYR) is taken up into NE nerve terminals via a
tyrosine transporter.
 In the cytosol, it is converted into DOPA by the enzyme
tyrosine hydroxylase (TOH).

4. Synthesis
 DOPA is then converted into dopamine (DA) by the
enzyme DOPA decarboxylase (DDC).
 DA is converted into NE by dopamine β-hydroxylase
(DBH).
 Disulfiram is an inhibitor of DBH.
 NE is packaged into synaptic vesicles via the
vesicular monoamine transporter 2 (VMAT2) and
stored until release.

5. Drugs Affecting Synthesis
Methyltyrosine inhibits tyrosine hydroxylase (used rarely to treat phaeochromocytoma)
Carbidopa, inhibits dopa decarboxylase used in the Rx of parkinsonism.
Methyldopa (used in treatment of HTN during pregnancy) is taken up by noradrenergic neurons,
where it is converted to the pseudotransmitter - α-methylnoradrenaline.

6. Release
Depolarisation of the nerve terminal
membrane
Opens calcium channels in the nerve
terminal membrane
Entry of Ca2+
The fusion of synaptic vesicles and
discharge of NA into synapse

7. Termination of Action
Norepinephrine’s action can be terminated through
multiple mechanisms.
1. Norepinephrine transporter (NET) / NE reuptake
pump
2. extracellularly via the enzyme catechol-O-
methyltransferase (COMT)
3. Monoamine oxidase A (MAO-A) and Monoamine
oxidase B (MAO-B) enzymes present in mitochondria
of presynaptic neurons, other neurons and glia.

8. Termination of Action
NE Transporters
 Belong to SLC6 gene family
 Norepinephrine is its endogenous substrate
 Dopamine, Epinephrine & Amphetamine are it’s false substrates.
 Psychostimulants, such as cocaine and the amphetamines, on DAT, these drugs also interact with
NET and intensify the synaptic actions of NE.

9. NE Transporters in Psychiatry
NE Transporters
 NET for norepinephrine is a key target for most of the known drugs that treat unipolar depression,
ADHD, and numerous other disorders ranging from anxiety to pain
 The mechanism of certain antidepressant drugs includes blockade of NET, such as
1. TCAs
2. the more specific serotonin–norepinephrine reuptake inhibitors (SNRIs) such as duloxetine
and venlafaxine,
3. norepinephrine– dopamine reuptake inhibitors (NDRIs) such as bupropion, and
4. selective norepinephrine reuptake inhibitors (NRIs), such as maprotiline and atomoxetine,
which is also used in the treatment of ADHD.

10. Metabolism
Catechol-o-methyl-transferase (COMT)
 Metabolises all catecholamines and their byproducts.
 Membrane-bound form and Soluble form.
 Membrane-bound COMT is the major form found in the CNS

11. Metabolism
Mono Amine Oxidase (MAO)
 It is located on the outer membranes of mitochondria
 Two isoforms of MAO (types A and B) - In brain, MAO-A -dopaminergic and noradrenergic
neurons, while MAO-B - serotonergic neurons and glia.
 Dopamine and norepinephrine are effective substrates for both forms, whereas serotonin is a
preferential substrate for MAO-A.
 Also present in liver and intestines.
 MAO inhibitors are used as antidepressants.

12. Metabolism
The final product formed by the sequential action of MAO and COMT is 3-hydroxy-4-
methoxyphenylglycol (MHPG).
This is partly conjugated & excreted in the urine, but most of it is converted to vanillylmandelic acid
(VMA) and excreted in the urine .
VMA levels are diagnostic for tumours and levels of MHPG are used to assess the functional status of
the noradrenergic system.

13. Noradrenergic neurons in CNS
 The noradrenergic innervation in the brain is mainly derived from a very small cluster of neurons
located in the locus coeruleus (LC, part of the pons)
 also from the lateral tegmental area (part of the midbrain).
LC norepinephrine neurons exhibit different activity modes:
 Tonic firing with short periods of burst firing: associated with the sleep–waking cycle,
 Phasic mode: occurs in response to arousing stimuli.

14. Noradrenergic neurons in CNS
The noradrenergic innervation in the brain is mainly derived from a very small cluster of neurons located
in the locus coeruleus (LC, part of the pons)
in addition to a more diffuse grouping in the lateral tegmental area (part of the midbrain).
LC norepinephrine neurons exhibit different activity modes:
 Tonic firing with short periods of burst firing: associated with the sleep–waking cycle,
 Phasic mode: occurs in response to arousing stimuli.

15. Noradrenergic functions in CNS
LC neurons project to the neocortex, hippocampus,
thalamus, midbrain tectum and spinal cord.
 Ascending LC projections regulate mood, arousal
and cognition.
 Descending LC projections extends down the spinal
cord regulate pain pathways.
 Through alpha 1 and alpha 2 receptors, respectively,
NE can have both pro- and anti-nociceptive effects,
by modulation of “on” and “off” cells of the
Rostroventral Medulla

16. Noradrenergic functions in CNS
 Projections to the sympathetic preganglionic neurons
in the spinal cord and parasympathetic preganglionic
neurons in the brainstem and spinal cord
 Regulation of Autonomic Nervous System
 Also effects the Endocrine System.
 GnRH release and Somatotropin or GH, is
stimulated by norepinephrine.

17. Noradrenergic functions in CNS
 Release of NE into cortical areas is associated
with wakefulness.
 Orexin/hypocretin stimulate release of NE
along with other neurotransmitters in daylight.
 As light fades, norepinephrine from the locus
coeruleus and serotonin from the raphe nuclei
build up and are released onto neurons in the
lateral hypothalamus, causing negative
feedback inhibiting the release of orexin.
 Norepiprephine prevents REM sleep, and lack of REM sleep increases noradrenaline secretion as
a result of the locus coeruleus overactivity. In chronic cases it causes neurodegeneration.

18. Noradrenergic receptors
 NE receptors are classified as α1, α2A, α2B, or α2C, or
as β1, β2, or β3.
 All are postsynaptic, α2 receptors can also act as
presynaptic autoreceptors.
 Presynaptic α2 autoreceptors cause a negative
feedback regulatory signal.
 The norepinephrine transporter and vesicular monoamine
transporter 2 (VMAT2).

19. Noradrenergic receptors
 (A) When they are not bound by norepinephrine, they are
open, allowing norepinephrine release.
 (B) When norepinephrine binds to the receptors, they
close the molecular gate and prevent norepinephrine
from being released.

20. Noradrenergic receptors

21. Noradrenergic receptors
 NA agonists are referred to as “sympathomimetics” and antagonists as “sympatholytics.”
 Clonidine is also used to manage the acute phase of opioid withdrawal, by normalizing the
hyperactivity of NA locus coeruleus neurons.
 Guanfacine - more selective α2A-agonist than Clonidine.
 used to treat a variety of disorders with prominent prefrontal cortex dysfunction, including Tourette
syndrome and ADHD.
 Yohimbine, α2 antagonist increases activity of locus coeruleus noradrenergic activity by blocking
autoreceptors, can induce symptoms of fear and anxiety in animals and humans.

22. Noradrenergic receptors
 NA agonists are referred to as “sympathomimetics” and antagonists as “sympatholytics.”
 β-Adrenergic antagonists, such as propranolol, are also used to reduce high levels of sympathetic
activity in individuals with anxiety disorders, such as hand tremor, sweating, and rapid heartbeat.

25. Specific Drugs and their effects
on Noradrenaline

26. Residual symptoms of depression can be linked to the
neurotransmitters that regulate them.
Fatigue and lack of concentration are regulated mostly by
norepinephrine (NE) and dopamine (DA), and therefore can be
treated by agents that increase NE and/or DA.

27. Quetiapine is the only one with any relevant monoamine
reuptake inhibition.
Specifically, it binds to the norepinephrine transporter
(NET) with similar potency as it does to the 5HT2A
receptor, and greater potency than to the D2 receptor.
Binding is primarily due to norquetiapine (a metabolite of
quetiapine)
Quetiapine’s pharmacological and binding profile.

28. Paroxetine:
An SSRI with Anti-Ach and Norepinephrine Transporter (NET)
Inhibitory Actions.
Venlafaxine is an SNRI that inhibits both the
serotonin transporter (SERT) and the
norepinephrine transporter (NET), thus combining
two therapeutic mechanisms in one agent.
Desvenlafaxine : NET action > SERT action

29. Duloxetine: Noradrenergic actions may contribute to
efficacy for painful physical symptoms.
Milnacipran: is a more potent inhibitor of NET than SERT.
The S enantiomer of milnacipran also known as levomilnacipran
is the active enantiomer.
approved for treatment of symptoms in fibromyalgia

30. Mirtazapine’s primary
therapeutic action is α2
antagonism
Mianserin has a similar
binding profile to mirtazapine,
the only
difference being additional
effects at α1
receptors.
NaSSA: noradrenergic and
specific serotonergic
antidepressant.

31. Ketamine is used off-label in treatment-resistantdepression.
It is an NMDA (N-methyl-D-aspartate) receptor antagonist, with
additional weak actions at
- σ1 receptors,
- the norepinephrine transporter (NET),
- μ-opioid receptors, and
- the serotonin transporter (SERT).

32. NE in Addiction
Binding of nicotine to receptors leads to the subjective
gratifying effects (through modulation of norepinephrine,
and other neurotransmitters) in the mesocorticolimbic
system.
The release of these neurotransmitters (via nicotine
receptors) leads to the experience of reinforcing effects of
smoking such as pleasure, arousal, appetite suppression
and subjective lessening of anxiety.

33. Bupropion is an Norepinephrine–dopamine reuptake inhibitor (NDRI) that
has weak blocking properties for the dopamine transporter (DAT) and for
the norepinephrine transporter (NET).
Its metabolites have antidepressant actions due to the more potent
inhibitory properties.

34. NET blockade in the prefrontal cortex leads to an increase in synaptic norepinephrine.
Because the prefrontal cortex lacks DATs, and NETs transport dopamine (DA) as well as NE, NET blockade also leads
to an increase in synaptic DA as well.
It does take the edge off and can makes abstinence more tolerable.

35. Norepinephrine provides input to the amygdala it plays an
important role in the fear response.
Noradrenergic hyperactivation can lead
to anxiety, panic attacks, tremors, sweating, tachycardia,
hyperarousal, and nightmares

36. Noradrenergic hyperactivity may
be blocked by the administration
of α1-adrenergic antagonists
or NET inhibitors, which can
lead to the alleviation of anxiety
and other stress-related
symptoms

37. • Clinical trials suggested that norepinephrine reuptake inhibitors may also have efficacy for the treatment of
comorbid PTSD and Anxiety Disorder.
• Noradrenergic medications for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine.

38. If descending NE inhibition is deficient, then it may not be
sufficient to mask irrelevant nociceptive input, leading to
perception of pain that is normally ignored.
This may be a contributing factor for painful somatic
symptoms in fibromyalgia, depression, irritable bowel
syndrome, other neuropathic pains.
SNRIs can increase noradrenergic neurotransmission in the
descending spinal pathway to the dorsal horn, and enhance
inhibition of pain perception.

39. Cognitive dysfunction in ADHD may be a result of low tonic
noradrenergic and dopaminergic firing.
Along with the arousal pathways, the prefrontal
cortex (PFC) is also the main brain area where imbalances
in norepinephrine (NE) occur in ADHD.
Methylphenidate blocks the norepinephrine transporter
(NET) and the dopamine transporter (DAT).
Atomoxetine is a selective norepinephrine reuptake
inhibitor used in ADHD and sometimes used in the treatment
of cognitive impairment and frontal lobe symptoms.

40. MONOAMINE INTERACTIONS

41. Monoamine interactions: Regulation of NE by Serotonin
Stimulation of 5HT1A receptors is inhibitory.
Serotonin binding at these receptors could reduce GABA output
and in turn disinhibit norepinephrine,
dopamine, and acetylcholine release.

42. Monoamine interactions: Regulation of NE by Serotonin
Stimulation of 5HT1B heteroreceptors on ACh, HA, DA, and
NE presynaptic neurons is inhibitory;
Thus, serotonin binding at these receptors could potentially
decrease the release of these neurotransmitters.
5HT3 receptors specifically inhibit the release
of norepinephrine at the cortical level.

43. Monoamine interactions: Regulation of NE by Serotonin
Agomelatine : Endogenous melatonin is a a 5HT2C antagonist on GABA
interneurons.
It prevents serotonin (5HT) from binding here and as a result releases
norepinephrine and dopamine in the prefrontal cortex.

44. 01
02
03
Kaplan and Sadock's Comprehensive Textbook of Psychiatry 10th edition
Stahl's Essential Psychopharmacology 5th edition
Maudsley Prescribing Guidelines in Psychiatry
References
04
Guyton and Hall Textbook of Medical Physiology 14th Edition

45. THANK YOU