Topic 7: Norepinephrine Flashcards
What is the process of synthesis of norepinephrine?
tyrosine hydroxylase (TH) converts dietary L-tyrosine into L-DOPA
DOPA decarboxylase converts L-DOPA into dopamine
DBH converts dopamine into norepinephrine
the presence of DBH determines if a cell makes DA or NE
How is catecholamine broken down?
catecholamine breakdown occurs by MAO or COMT
major metabolic end-products are vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxy phenylglycol (MHPG)
levels of MHPG in the CSF or VMA in urine can be used to assess catbolism of catecholamines
What are the characteristics of the noradrenergic synapse?
NE is synthesized in vesicles from dopamine via dopamine-beta-hydroxylase (D beta H)
after release, NE is recycled into the cell by the NE transporter (NET)
NE is catabolized by MAO and COMT or is recycled into vesicles through the vesicular monoamine transporter (VMAT)
What are adrenergic receptors?
norepinephrine and epinephrine bind and activate adrenergic receptors
metabotropic receptors - G-protein coupled
responsible for both CNS effects (neurotransmitters) and peripheral effects (autonomic/hormones)
function as post-synaptic receptors and as presynaptic autoreceptors
What are agonists of adrenergic receptors?
agonists of adrenergic receptors are sympathomimetic
mimic sympathetic nervous system
What are antagonists of adrenergic receptors?
antagonists of adrenergic receptors are sympatholytic
block sympathetic nervous system
What are alpha-adrenergic receptors?
alpha1 –> coupled to Gq alpha
alpha2 –> coupled to Gi alpha
phenylephrine is selective agonist (alpha 1/2)
vasoconstriction
agonists at alpha2 receptors can lower blood pressure - CNS acting
What are agonists at the alpha2 adrenergic receptors?
alpha2 receptors in the brainstem (vasomotor center) are autoreceptors: inhibit release of more NE
clonidine prescribed to treat hypertension
side effects include sedation, drowsiness
also effective treatment for ADHD by increasing NE tone in the PFC at postsynaptic alpha2A receptors
What are beta-adrenergic receptors?
B1 –> coupled to Gs alpha
B2 –> mostly coupled to Gs alpha
B3 –> coupled to Gs alpha
isoprenaline is selective agonist (beta 1/2/3)
vasodilation
agonists at beta-adrenergic receptors relax bronchial muscles
What are agonists at the beta adrenergic receptors?
albuterol is a specific beta-adrenoceptor agonist used to treat asthma
delivered via inhalation (direct effects at site of absorption, avoids effects on heart)
antagonists at beta1 receptors affect heart rate and contractile force
metoprolol is a selective beta1 receptor antagonist (beta-blocker) used to treat arrhythmia and angina pectoris
Where are noradrenergic projections in the brain?
noradrenergic projections emanate from the locus coeruleus (brainstem/pons) to many areas of the brain
small region (3000 neurons), big impact on behavior
Where in the brain is norepinephrine involved with arousal?
noradrenergic projections innervate regions involved in arousal, attention, and vigilance
medial septum
Where in the brain is norepinephrine involved with eating?
norepinephrine affects eating behaviors
paraventricular nucleus (hypothalamus)
Where in the brain is norepinephrine involved with depression?
noradrenergic pathways innervate areas involved in depression
limbic cortex, amygdala, hippocampus
What were the results of the animal model of vigilance and norepinephrine?
locus coeruleus activity recorded in awake, free moving animals
low firing rates: sleep, grooming, eating
novel sensory stimuli resulted in short burst activity in LC
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
Is activity in locus coeruleus connected to norepinephrine?
selective agonists for alpha and beta adrenoreceptors increase awake time when microinjected into the medial septum
cumulative effects suggest both receptor systems are involved in normal functioning
Is activity in the hypothalamus connected to norepinephrine?
microinjection of norepinephrine into the hypothalamus (paraventricular nucleus) stimulates eating behavior even in food-satiated rats
What are the specific roles of norepinephrine in depression?
adrenergic system is shown to be altered in depressed patients
antidepressants: can act on adrenergic receptors (predominantly alpha1), 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)
What is the monoamine hypothesis of depression?
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 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
What are tricyclic antidepressants (TCA)?
developed in the 1950’s from chlorpromaxine analogues
imipramine (Tofranil) is an inhibitor of both norepinephrine transporters (NET) and 5-HT transporters (SERT)
impaired reuptake leads to elevated synaptic NE/5-HT
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 in higher doses
What are selective serotonin reuptake inhibitors (SSRIs)?
second generation antidepressants - targeted drug design
fluoxetine (Prozac, 1987) most widely prescribed
selective inhibitors for SERT
5-HT accumulates in the synapse, enhancing post-synaptic activity
What are serotonin-norepinephrine reuptake inhibitors (SNRI)?
second generation antidepressant - replaces TCA
first SNRI was venlafaxine (Effexor, 1994)
inhibits both SERT and NET
fewer side effects than TCAs, improved safety margin
What are the 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
demonstrated 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
inconsistent findings in antidepressant effects of amino acid precursors to NA/5-HT (e.g., tyrosine and tryptophan)
What are selective norepinephrine reuptake inhibitors?
norepinephrine reuptake inhibitors represent the third class of 2nd generation antidepressants brought to the market
selectivity of ~20x for NET (NE transporter) over SERT (5-HT reuptake transporter)
