Norepinephrine Flashcards by Cambell Meier

norepinephrine synthesis

L-tyroseine —TH–> L-DOPA —DOPA decarboxylase –> dopamine –DBH–>norepinephrine — PNMT –> epinephrine

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Catecholamine breakdown occurs by

MAO or COMT

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Major metabolic end-products from norepinephrine breakdown are

(VMA), (MHPG).

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Levels of MHPG in the CSF or VMA in urine can be used to assess

catabolism of catecholamines.

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Noradrenergic synapse NE is synthesized in

in vesicles from dopamine via dopamine-β-hydroxylase (DβH).

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Noradrenergic synapse After release, NE is

recylced into the cell by the NE transporter (NET).

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NE is catabolised by

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Norepinephrine and epinephrine bind and activate

adrenergic receptors

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Metabotropic receptors

G-protein coupled

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adrenergic receptors Responsible for both

CNS effects (neurotransmitters) and peripheral effects (autonomic / hormones)

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adrenergic receptors Function as

post-synaptic receptors and as presynaptic autoreceptors

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Agonists of adrenergic receptors are

sympathomimetic

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Antagonists of adrenergic receptors are

sympatholytic

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α1 – coupled to

Gqα

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α2 – coupled to

Giα

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Phenylephrine is

is selective agonist (α1/2)

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α1 – coupled to Gqα
α2 – coupled to Giα

Vasoconstriction

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Agonists at α2 receptors can

lower blood pressure – CNS acting

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α2 receptors in the brainstem (vasomotor centre) are

autoreceptors

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Clonidine prescribed to treat

hypertension

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β1 – coupled to

Gsα

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β2 – mostly coupled to

Gsα

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β3 – coupled to

Gsα

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Isoprenaline is

is selective agonist (β1/2/3)

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β1 – coupled to Gsα β2 – mostly coupled to Gsα β3 – coupled to Gsα

Vasodilation

Agonists at β-adrenergic receptors

relax bronchial muscles

Albuterol

is a specific β-adrenoceptor agonist used to treat asthma

Metoprolol is a selective

β1 receptor antagonist (β-blocker) used to treat arrhythmia and angina pectoris

Noradrenergic projections emanate from the

the locus coeruleus

locus coeruleus

Small region (3000 neurons), big impact on behaviour

Noradrenergic projections innervate regions involved in

arousal, attention, and vigilance

Norepinephrine affects

eating behaviours

Paraventricular nucleus (hypothalamus) tell you when youre

hungry/not

Noradrenergic pathways innervate areas involved in

depression

Noradrenergic pathways innervate areas involved in depression

Limbic cortex, amygdala, hippocampus

LC adrenergic neurons part of the

reticular activating system

LC adrenergic neurons part of the reticular activating system

Fire when awake or slow wave sleep Inactive in REM sleep Slow breakdown of NE might account for latency during changes of consciousness

Selective agonists for α and β adrenoreceptors increase awake time when microinjected into the

medial septum. indicating that both receptor systems are involved in normal functioning.

Antidepressants Can act on

adrenergic receptors (predominantly α1)

Antidepressants Often target

norepinephrine reuptake or breakdown

Monoamine neurotransmitters are a common target for

antidepressants

MAOI antidepressants reduce the breakdown of

all monoamine NTs (dopamine, norepinephrine, serotonin)

The Monoamine Hypothesis

Depression is a result of a functional deficit of the neurotransmitters norepinephrine and serotonin (5-HT) at specific synapses in the CNS

First antidepressant was a

a monoamine oxidase inhibitor (MAOI), iproniazad, an anti-tuberculosis drug (1952)

MAOI cause elevation of

monoamines by inhibiting their catabolism

Elevated monoamines leads to increases in

monaminergic neurotransmission (dopamine, norepinephrine, serotonin[ 5-HT])

Phenylzine was the most common

MAOI in use clinically Discontinued due to the cheese effect

Imipramine (Tofranil) is an

inhibitor of both norepinephrine transporters (NET) and 5-HT transporters (SERT)

Sustained NE/5-HT levels lead to

prolonged and increased post-synaptic activity

Side effects on muscarinic receptors (anti-cholinergic)

Parasympatholytic – dry mouth, constipation, urinary retention

Poor safety margin

induces mania at higher doses

SSRI

Selective serotonin reuptake inhibitors

Fluoxetine (Prozac, 1987)

SSRI

SSRI actions

5-HT accumulates in the synapse, enhancing post-synaptic activity

SNRI

Serotonin-norepinephrine reuptake inhibitors

First SNRI was

venlafaxine (Effexor, 1994)

SSRI Selective inhibitors for

SERT

SNRI Inhibits both

SERT NET

SNRI Fewer

side effects than TCAs, improved safety margin

Challenges to the Monoamine hypothesis

Pharmacologic effects are very rapid (hours-days) but therapeutic effects are slow (weeks-months) Monoamines normalize rapidly, but mood normalizes slowly

efficacy of drugs that do not affect NA/5-HT reuptake

Tianeptine, a selective serotonin reuptake enhancer is equally effective as SSRIs in clinical trials

Cocaine (potent NA reuptake inhibitor)

does not have antidepressant effects

Norepinephrine reuptake inhibitors represent the third class of

2nd generation antidepressants brought to market

Norepinephrine reuptake inhibitors represent the third class of 2nd generation antidepressants brought to market First was

reboxetine (Edronax/Prolift) in 1997

NE reuptake inhibitors are

psychostimulants

NE reuptake inhibitors are psychostimulants

Absence of activity at the dopamine transporter prevents addictive effects of psychomotor stimulants (e.g. cocaine)

Noradrenergic drugs have been demonstrated effective in treating

attention deficit hyperactivity disorder (ADHD)

Clonidine

α2A agonist increases NE tone in the PFC

Reboxetine

NET inhibitor

Clonidine – α2A agonist increases NE tone in the PFC Reboxetine – NET inhibitor

Thought to act to increase / prolong NE signalling to cortex, affecting attention

Withdrawal from opioids (heroin, morphine) activates the

noradrenergic system

Withdrawal from opioids (heroin, morphine) activates the noradrenergic system

Responsible for withdrawal effects such as increased heart rate, elevated blood pressure, and diarrhea

α2 receptors are targets to treat symptoms of

opioid withdrawal

Clonidine is an

α2 agonist that is used clinically to treat opioid withdrawal symptoms

α2 receptors in the brainstem function as

presynaptic autoreceptors on noradrenergic cells – activation decreases the release of NE

Yohimbine

is an α2 antagonist that can be used experimentally to increase/provoke withdrawal symptoms

IV administration of yohimbine

rapidly increases the severity of opioid withdrawal, and increases anxiety in patients (sometimes to the point of panic attacks), suggesting NE may also be involved in generating feelings of anxiety. Many antidepressants also have anxiolytic activites.