Topic 7: Norepinephrine

Question 1

What is the process of synthesis of norepinephrine?

Answer 1

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

Question 2

How is catecholamine broken down?

Answer 2

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

Question 3

What are the characteristics of the noradrenergic synapse?

Answer 3

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)

Question 4

What are adrenergic receptors?

Answer 4

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

Question 5

What are agonists of adrenergic receptors?

Answer 5

agonists of adrenergic receptors are sympathomimetic

mimic sympathetic nervous system

Question 6

What are antagonists of adrenergic receptors?

Answer 6

antagonists of adrenergic receptors are sympatholytic

block sympathetic nervous system

Question 7

What are alpha-adrenergic receptors?

Answer 7

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

Question 8

What are agonists at the alpha2 adrenergic receptors?

Answer 8

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

Question 9

What are beta-adrenergic receptors?

Answer 9

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

Question 10

What are agonists at the beta adrenergic receptors?

Answer 10

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

Question 11

Where are noradrenergic projections in the brain?

Answer 11

noradrenergic projections emanate from the locus coeruleus (brainstem/pons) to many areas of the brain

small region (3000 neurons), big impact on behavior

Question 12

Where in the brain is norepinephrine involved with arousal?

Answer 12

noradrenergic projections innervate regions involved in arousal, attention, and vigilance

medial septum

Question 13

Where in the brain is norepinephrine involved with eating?

Answer 13

norepinephrine affects eating behaviors

paraventricular nucleus (hypothalamus)

Question 14

Where in the brain is norepinephrine involved with depression?

Answer 14

noradrenergic pathways innervate areas involved in depression

limbic cortex, amygdala, hippocampus

Question 15

What were the results of the animal model of vigilance and norepinephrine?

Answer 15

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

Question 16

Is activity in locus coeruleus connected to norepinephrine?

Answer 16

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

Question 17

Is activity in the hypothalamus connected to norepinephrine?

Answer 17

microinjection of norepinephrine into the hypothalamus (paraventricular nucleus) stimulates eating behavior even in food-satiated rats

Question 18

What are the specific roles of norepinephrine in depression?

Answer 18

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)

Question 19

What is the monoamine hypothesis of depression?

Answer 19

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

Question 20

What are tricyclic antidepressants (TCA)?

Answer 20

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

Question 21

What are selective serotonin reuptake inhibitors (SSRIs)?

Answer 21

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

Question 22

What are serotonin-norepinephrine reuptake inhibitors (SNRI)?

Answer 22

second generation antidepressant - replaces TCA

first SNRI was venlafaxine (Effexor, 1994)

inhibits both SERT and NET

fewer side effects than TCAs, improved safety margin

Question 23

What are the challenges to the monoamine hypothesis?

Answer 23

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)

Question 24

What are selective norepinephrine reuptake inhibitors?

Answer 24

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)

Question 25

What were the results of the 2009 meta-analysis questioned the efficacy of reboxetine?

Answer 25

found that it doesn’t work better than placebo

in a more thorough systematic review that included unpublished research data from Pfizer

74% of patient data from the original Pfizer trials was previously unpublished

reboxetine found to be indistinguishable from placebo

significantly more adverse consequences

Question 26

How are noradrenergic drugs used to treat attention disorders?

Answer 26

NE reuptake inhibitors are psychostimulants: absence of activity at the norepinephrine transporter prevents addictive effects of psychomotor stimulants (e.g., cocaine)

noradrenergic drugs have been demonstrated effective in treating attention deficit hyperactivity disorder (ADHD)

clonidine - alpha2A agonist increases NE tone in the PFC
reboxetine - NET inhibitor

thought to act to increase/prolong NE signaling to cortex, affecting attention

Question 27

How does norepinephrine contribute to opioid withdrawal?

Answer 27

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

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

alpha2 receptors are targets to treat symptoms of opioid withdrawal

clonidine is an alpha2 agonist that is used clinically to treat opioid withdrawal symptoms

alpha2 receptors in the brainstem function as presynaptic autoreceptors on noradrenergic cells - activation decreases the release of NE

Yohimbine is an alpha2 antagonist that can be used experimentally to increase/provoke withdrawal symptoms

Question 28

What is yohimbine?

Answer 28

IV administration of yohimbine rapidly increases the severity of opioid withdrawal, and increases anxiety in patients, sometimes to the point of panic attacks

suggesting norepinephrine may also be involved in generating feelings of anxiety

many antidepressants also have anxiolytic activities