Norepinephrine (NE)

Question 1

Describe catecholamine breakdown

Answer 1

• 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 catabolism of catecholamines.

Question 2

Describe noradrenergic synapse

Answer 2

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

After release, NE is recylced into the cell by the NE transporter (NET).

NE is catabolised by MAO and COMT or is recycled into vesicles through the vesicular monoamine transporter (VMAT).

Question 3

Describe adrenergic receptors

Answer 3

• 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 4

Describe noradrenergic sympathomimetics

Answer 4

Agonists of adrenergic receptors are sympathomimetic

Question 5

Describe noradrenergic sympatholytics

Answer 5

Antagonists of adrenergic receptors are sympatholytic

Question 6

Describe alpha adrenergic receptors

Answer 6

• α1 – coupled to Gqα
• α2 – coupled to Giα
• Phenylephrine is selective agonist (α1/2)
• 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
• Side effects include sedation, drowsiness
• Also effective treatment for ADHD by increasing NE tone in the PFC at postsynaptic α2A receptors

Question 7

Describe beta adrenergic receptors

Answer 7

• β1 – coupled to Gsα
• β2 – mostly coupled to Gsα
• β3 – coupled to Gsα
• Isoprenaline is selective agonist (β1/2/3)
• Vasodilation
• Agonists at β-adrenergic receptors relax bronchial muscles
• Albuterol is a specific β-adrenoceptor agonist used to treat asthma
• Delivered via inhalation (direct effects at site of absorption, avoids effects on heart)
• Antagonists at β1 receptors affect heart rate and contractile force
• Metoprolol is a selective β1 receptor antagonist (β-blocker) used to treat arrhythmia and angina pectoris

Question 8

Where do noradrenergic receptors come from?

Answer 8

• Noradrenergic projections emanate from the locus coeruleus (brainstem/pons) to many areas of the brain
• Small region (3000 neurons), big impact on behaviour

Question 9

Describe norepinephrine

Answer 9

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

• Medial septum
  Norepinephrine affects eating behaviours
• Paraventricular nucleus (hypothalamus)
  Noradrenergic pathways innervate areas involved in
  depression
• Limbic cortex, amygdala, hippocampus

Question 10

Describe vigilance

Answer 10

LC 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 11

Describe selective agonists

Answer 11

• Selective agonists for α and β adrenoreceptors increase awake time when microinjected into the medial septum.
• Cumulative effects suggest both receptor systems are involved in normal functioning.

Question 12

Describe microinjection of NE

Answer 12

• Microinjection of NE into the hypothalamus (paraventricular nucleus) stimulates eating behaviour even in food- satiated rats.

Question 13

Describe specific roles of ne in depression

Answer 13

• Adrenergic system is shown to be altered in depressed patients
• Antidepressants
• Can act on adrenergic receptors (predominantly α1)
• 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 14

Describe monoamine hypothesis

Answer 14

DEPRESSION IS A RESULT OF A FUNCTIONAL DEFICIT OF THE NEUROTRANSMITTERS NOREPINEPHRINE AND SEROTONIN (5-HT) AT SPECIFIC SYNAPSES IN THE CNS

Question 15

Describe monoamine hypothesis in detail

Answer 15

• 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 16

Describe TCA

Answer 16

• Developed in the 1950’s from chlorpromazine 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 at higher doses

Question 17

Describe SSRIs

Answer 17

• Selective serotonin reuptake inhibitors
• 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 18

Describe SNRIs

Answer 18

• Serotonin-norepinephrine reuptake inhibitors
• Second generation antidepressant – replaces TC A
• First SNRI was venlafaxine (Effexor, 1994)
• Inhibits both SERT and NE T
• Fewer side effects than TCAs, improved safety margin

Question 19

Describe challenges to the monamine hypothesis

Answer 19

• 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 20

Describe SELECTIVE NE REUPTAKE INHIBITORS

Answer 20

• Norepinephrine reuptake inhibitors represent the third class of 2nd generation
  antidepressants brought to market
• First was reboxetine (Edronax/Prolift) in 1997
• Selectivity of ~20x for NET (NE transporter) over SERT (5-HT reuptake transporter)
• [Not brought to market in USA or Canada]
• 2009 meta-analysis questioned the efficacy of reboxetine

Question 21

Describe systematic review

Answer 21

• 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
• Study author’s conclusion:
• “Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.”

Question 22

Describe attention disorders

Answer 22

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

Question 23

Describe how NE contributes to opioid withdrawal

Answer 23

• 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

Question 24

Describe IV admin of yohimbine

Answer 24

• 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.