Norepinephrine Flashcards
norepinephrine synthesis
L-tyroseine —TH–> L-DOPA —DOPA decarboxylase –> dopamine –DBH–>norepinephrine — PNMT –> epinephrine
Catecholamine breakdown occurs by
MAO or COMT
Major metabolic end-products from norepinephrine breakdown are
(VMA), (MHPG).
Levels of MHPG in the CSF or VMA in urine can be used to assess
catabolism of catecholamines.
Noradrenergic synapse NE is synthesized in
in vesicles from dopamine via dopamine-β-hydroxylase (DβH).
Noradrenergic synapse After release, NE is
recylced into the cell by the NE transporter (NET).
NE is catabolised by
NE is catabolised by
Norepinephrine and epinephrine bind and activate
adrenergic receptors
Metabotropic receptors
G-protein coupled
adrenergic receptors Responsible for both
CNS effects (neurotransmitters) and peripheral effects (autonomic / hormones)
adrenergic receptors Function as
post-synaptic receptors and as presynaptic autoreceptors
Agonists of adrenergic receptors are
sympathomimetic
Antagonists of adrenergic receptors are
sympatholytic
α1 – coupled to
Gqα
α2 – coupled to
Giα
Phenylephrine is
is selective agonist (α1/2)
α1 – coupled to Gqα
α2 – coupled to Giα
Vasoconstriction
Agonists at α2 receptors can
lower blood pressure – CNS acting
α2 receptors in the brainstem (vasomotor centre) are
autoreceptors
Clonidine prescribed to treat
hypertension
β1 – coupled to
Gsα
β2 – mostly coupled to
Gsα
β3 – coupled to
Gsα
Isoprenaline is
is selective agonist (β1/2/3)
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.
