Noradrenaline Synthesis & Neurotransmission

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Questions and Answers

Which of the following best describes the mechanism by which amphetamine exerts its sympathomimetic effects?

  • Blocking adrenergic receptors, preventing norepinephrine from binding.
  • Inhibiting the enzymatic breakdown of norepinephrine by COMT.
  • Inhibiting the reuptake of norepinephrine from the synapse, increasing its concentration.
  • Promoting the premature release of norepinephrine from vesicles into the synaptic cleft. (correct)

A researcher is studying a novel compound that increases norepinephrine levels in the synapse. If the compound acts by inhibiting the enzyme responsible for breaking down norepinephrine inside the neuron, which enzyme is most likely being targeted?

  • Monoamine oxidase (MAO) (correct)
  • Catechol-O-methyltransferase (COMT)
  • Choline acetyltransferase (ChAT)
  • Acetylcholinesterase (AChE)

A patient is prescribed a medication that inhibits the storage of norepinephrine in vesicles. Which of the following effects would most likely be observed in this patient?

  • Increased metabolism of norepinephrine in the synaptic cleft by COMT.
  • Decreased sympathetic nervous system activity due to reduced availability of norepinephrine for release. (correct)
  • Selective blockade of alpha-1 adrenergic receptors in blood vessels.
  • Increased sympathetic nervous system activity due to enhanced release of norepinephrine.

A drug that inhibits choline reuptake at the synapse would directly lead to which of the following?

<p>Decreased synthesis of acetylcholine due to reduced availability of choline. (C)</p> Signup and view all the answers

What is the primary mechanism by which botulinum toxin affects neurotransmission?

<p>Inhibiting the release of acetylcholine, leading to muscle paralysis. (A)</p> Signup and view all the answers

Which of the following is the correct sequence of steps in the synthesis of norepinephrine, starting from its initial precursor?

<p>Tyrosine → DOPA → Dopamine → Norepinephrine (D)</p> Signup and view all the answers

Alpha-methyl tyrosine is a drug known to interfere with norepinephrine synthesis. Which of the following mechanisms best describes its action?

<p>Inhibiting the conversion of tyrosine to DOPA, thus reducing norepinephrine production. (D)</p> Signup and view all the answers

Which of the following physiological responses is primarily mediated by stimulation of alpha-2 adrenergic receptors?

<p>Inhibition of norepinephrine release from presynaptic terminals. (B)</p> Signup and view all the answers

A patient experiencing bronchoconstriction might benefit from a medication that selectively activates which type of adrenergic receptor?

<p>Beta-2 adrenergic receptors. (A)</p> Signup and view all the answers

Which of the following effects would be expected from the administration of a selective beta-1 adrenergic receptor antagonist?

<p>Decreased heart rate and force of contraction. (C)</p> Signup and view all the answers

In the context of neurotransmission, what is the functional role of choline acetyltransferase (ChAT)?

<p>Synthesis of acetylcholine from acetyl-CoA and choline. (D)</p> Signup and view all the answers

Which of the following accurately describes the mechanism of action of vesamicol?

<p>It inhibits the storage of acetylcholine in vesicles. (A)</p> Signup and view all the answers

Latrotoxin, found in black widow spider venom, primarily affects neurotransmission by which mechanism?

<p>Causing a massive release of acetylcholine, followed by depletion. (D)</p> Signup and view all the answers

Activation of M3 muscarinic receptors typically leads to which of the following physiological effects?

<p>Increased salivation, lacrimation, and gastrointestinal motility. (B)</p> Signup and view all the answers

Atropine, a muscarinic antagonist, is likely to cause which of the following effects?

<p>Decreased gastrointestinal motility and decreased salivation. (C)</p> Signup and view all the answers

Neostigmine is an acetylcholinesterase inhibitor. What effect will it have on acetylcholine levels and cholinergic neurotransmission?

<p>Increased acetylcholine levels, leading to enhanced cholinergic neurotransmission. (C)</p> Signup and view all the answers

Hemicholinium inhibits choline reuptake into the presynaptic neuron. What direct effect would this have on acetylcholine neurotransmission?

<p>Decreased synthesis of acetylcholine due to reduced availability of choline. (B)</p> Signup and view all the answers

Which of the following best characterizes the function of nicotinic neuronal (Nn) receptors found in the adrenal medulla?

<p>Release of adrenaline and noradrenaline into the bloodstream. (A)</p> Signup and view all the answers

Activation of beta-3 adrenergic receptors in adipose tissue leads to which of the following effects?

<p>Increased lipolysis and release of fatty acids. (B)</p> Signup and view all the answers

Which of the following receptors mediates the contraction of the internal urinary sphincter, contributing to urinary continence?

<p>Alpha-1 adrenergic receptors. (C)</p> Signup and view all the answers

The increased uptake of K+ by skeletal muscles is mediated by which of the following receptors?

<p>Beta-2 adrenergic receptors (B)</p> Signup and view all the answers

Which of the following is a degradation product (metabolite) of norepinephrine that can be found in urine?

<p>VMA (A)</p> Signup and view all the answers

Which type of acetylcholine receptor is primarily responsible for skeletal muscle contraction?

<p>Nicotinic Muscular (Nm) (B)</p> Signup and view all the answers

Which receptor type, when stimulated, leads to increased sweat production (diaphoresis) via the sympathetic nervous system?

<p>Muscarinic (M3) (B)</p> Signup and view all the answers

What is the effect of stimulating Beta 1 receptors on the kidney?

<p>Increased blood pressure (C)</p> Signup and view all the answers

Flashcards

Noradrenaline Synthesis Pathway

Tyrosine → DOPA → Dopamine → Noradrenaline (or Norepinephrine)

Steps of Adrenergic Neurotransmission

  1. Synthesis of NE. 2. NE is stored in vesicles. 3. Released into gap upon nerve stimulation. 4. Acts on adrenergic receptors. 5. NE Reuptake. 6. Repackaged and stored again OR broken down by enzymes (MOA, COMT).

MOA and COMT

Enzymes that catalyze the breakdown of norepinephrine (NE). MOA is inside the neuron, COMT is outside the neuron.

Nor-Adrenaline Metabolites

VMA and MOPEG are metabolites found in urine resulting from noradrenaline (NA) and norepinephrine (NE) metabolism.

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Alpha-methyl tyrosine/DOPA

Inhibits noradrenaline synthesis, leading to a decrease in stored and released NA, thus decreasing sympathetic effects.

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Reserpine

Inhibits NE storage in vesicles, decreasing NE release and sympathetic effects.

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Amphetamine

Causes premature release of NE from vesicles into the synaptic cleft, increasing NE levels and mimicking the effects of the sympathetic nervous system.

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Guanethidine

Inhibits NE release, leading to decreased sympathetic effects.

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Dobutamine

Selectively stimulates beta-1 adrenergic receptors, increasing sympathetic system effects, particularly in the heart.

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Metoprolol

Selectively blocks beta-1 adrenergic receptors, decreasing sympathetic effects, particularly in the heart.

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Cocaine, Tricyclic Antidepressants

Inhibit the reuptake of noradrenaline from the synapse, leading to increased NE levels and sympathetic effects.

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Pargyline (MOA inhibitor)

Inhibits the enzymatic breakdown of noradrenaline, increasing the amount of NE stored within vesicles, leading to increased sympathetic effects.

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ChAT Enzyme

Choline acetyltransferase (ChAT) catalyzes the synthesis of acetylcholine (ACh) from acetyl-CoA and choline.

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Synthesis of Acetylcholine

Acetyl CoA + choline = ACh (with ChAT enzyme)

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Vesamicol

Inhibits ACh storage in vesicles, decreasing ACh release and effects.

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Latrotoxin (Black Widow Spider Venom)

Causes increased ACh release followed by inhibition, eventually leading to muscle paralysis due to ACh depletion.

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Botulinum Toxin

Inhibits ACh release, leading to decreased ACh release and muscle paralysis.

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Muscarine

Stimulates muscarinic cholinergic receptors, primarily affecting the parasympathetic system.

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Atropine

Blocks muscarinic cholinergic receptors, primarily affecting the parasympathetic system.

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Neostigmine

Inhibits the enzymatic breakdown of ACh, leading to increased ACh levels.

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Hemicholinium

Inhibits choline reuptake, leading to decreased ACh synthesis.

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Adrenergic Receptor Types

Alpha and Beta receptors

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Parasympathetic Receptor Type

M (muscarinic) receptors

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Somatic Receptor Type

N (nicotinic) receptors

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Alpha 1 Function on Blood Vessels

Vasoconstriction

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Study Notes

Noradrenaline Synthesis Pathway

  • The synthesis pathway includes: Tyrosine, DOPA, Dopamine, and Nor-adrenaline (or Nor-epinephrine)

Steps of Adrenergic Neurotransmission

  • Synthesis of NE
  • NE is stored in vesicles
  • NE is released into the gap, upon nerve stimulation
  • NE acts on adrenergic receptors
  • NE reuptake occurs into the presynaptic neuron
  • NE is repackaged and stored again, or broken down by enzymes (MAO, COMT)

Enzymes That Inactivate NE

  • Monoamine Oxidase (MOA): Located inside the neuron
  • Catechol-O-methyltransferase (COMT): Located outside the neuron (extraneuronal)

Degradation Products (metabolites) of Noradrenaline

  • Vanillylmandelic acid (VMA)
  • Methoxyhydroxyphenylglycol (MOPEG)
  • These metabolites are found in urine as a result of noradrenaline metabolism.

Drugs Affecting Adrenergic Neurotransmission - Synthesis Inhibitors

  • Alpha-methyl tyrosine and alpha-methyl DOPA inhibit synthesis.
  • They lead to the synthesis of a false neurotransmitter (alpha-methyl NE).
  • This false neurotransmitter has very little agonist activity.
  • Results in decreased noradrenaline stored and released, decreasing sympathetic effects on target tissues.

Inhibitor of NE Storage

  • Reserpine decreases NE release, leading to decreased sympathetic effects.

Displacement

  • Amphetamine causes premature release of NE from vesicles into the synaptic cleft.
  • Leads to increased NE levels in the synapse, mimicking the effects of the sympathetic nervous system (sympathomimetic effect).

Inhibitor of Release

  • Guanethidine decreases sympathetic effects by inhibiting NE release.

Adrenergic Receptor Agonists

  • Dobutamine stimulates beta-1 adrenergic receptors selectively.
  • This leads to increased sympathetic system effects due to its action on beta-1 adrenergic receptors.

Adrenergic Receptor Antagonists

  • Metoprolol selectively blocks beta-1 adrenergic receptors.
  • Leads to a decreased sympathetic effect.

NE Reuptake Inhibitors

  • Cocaine and tricyclic antidepressants increase levels of noradrenaline.
  • Results in increased sympathetic effects.

Inhibitors of Enzymatic Breakdown

  • Pargyline (MAO inhibitor) increases NE stored within vesicles.
  • This leads to increased sympathetic effects.

Synthesis of Acetylcholine Neurotransmitters

  • Choline acetyltransferase (ChAT) synthesizes ACh from acetyl-CoA and choline.
  • ChAT is located in the presynaptic terminals of nerve cells.

Steps of Cholinergic Neurotransmission

  • Acetyl CoA + choline = ACh, using the ChAT enzyme
  • ACh is stored in vesicles
  • ACh is released into the gap upon stimulation
  • ACh acts on nicotinic (N) or muscarinic (M) receptors
  • ACh is broken down by acetylcholinesterase (AChE) into choline and acetate
  • Choline is reuptaken into the presynaptic neuron, acetate diffuses away.

Drugs Affecting Cholinergic Neurotransmission - Inhibitor of ACh Storage

  • Vesamicol decreases ACh release, leading to decreased effects.

Displacement

  • Latrotoxin (black widow spider venom) causes increased ACh release, followed by complete inhibition of ACh release, eventually leading to muscle paralysis.
  • This is because the presynaptic neuron gets depleted of ACh
  • The effect is not permanent, occurring until ACh resynthesizes

Inhibitor of Release

  • Botulinum toxin decreases ACh release and can cause muscle paralysis.

Cholinergic Receptor Agonists

  • Muscarine stimulates muscarinic cholinergic receptors.
  • Primarily affects the parasympathetic system.

Cholinergic Receptor Antagonists

  • Atropine blocks muscarinic cholinergic receptors.
  • Primarily affects the parasympathetic system.

Inhibitors of Enzymatic Breakdown

  • Neostigmine (anticholinesterase) increases ACh levels.

Inhibitor of Choline Reuptake

  • Hemicholinium decreases the synthesis of ACh.

Identification of Receptor Types

  • Sympathetic Nervous System:

    • NE acts on alpha and beta receptors, affecting smooth muscle
    • ACh acts on muscarinic receptors, affecting glands
    • Epinephrine acts on alpha and beta receptors
    • ACh acts on nicotinic receptors on the adrenal medulla for epinephrine release

  • Parasympathetic Nervous System:

    • ACh acts on muscarinic receptors

  • Somatic System:

    • ACh acts on nicotinic receptors

Adrenergic Receptors (Sympathetic)

  • ACh → N → NE → Alpha and Beta receptors
  • ACh → N → Epi → Alpha and Beta receptors

Alpha 1 Receptors

  • Function: CONSTRICTION
    • Blood vessels (skin, abdomen): Vasoconstriction
    • Internal urinary sphincter: Contraction
    • Penis: Ejaculation
    • Piloerector muscles (hair): Contraction
    • Salivary glands: Thick, viscous secretions
    • Eye (radial muscle): Contraction (mydriasis; dilation)

Alpha 2 Receptors

  • Function: INHIBITION
    • Presynaptic: Inhibition of noradrenaline release (negative feedback)
    • Limits further NE release to avoid overstimulation of the target cells
    • Pancreas: Decreased insulin secretion
    • Gastrointestinal tract: Decreased secretions

Beta 1 Receptors

  • Function: STIMULATE HEART
    • Heart: Increased heart rate, increased force of contraction, increased conduction velocity
    • Kidney: Increased blood pressure by releasing renin

Beta 2 Receptors

  • Function: SMOOTH MUSCLE RELAXATION
    • Lungs, uterus, bladder (detrusor): Relaxation
    • Blood vessels (muscles, coronaries): Dilation
    • Liver: Glycogenolysis and gluconeogenesis
    • Gastrointestinal tract: Decreased motility (relaxation)
    • Skeletal muscles: Increased uptake of K+

Beta 3 Receptors

  • Function: Release and Relaxation.
    • Adipose tissue: Lipolysis
    • Bladder (detrusor): Relaxation

Cholinergic (ACh) Receptors

  • ACh → N (somatic)
  • ACh → N → ACh → M (sweat)
  • ACh → N → Epi → Alpha or Beta (sympathetic)

Types of Cholinergic Receptors

  • Can bind to two subtypes of receptors, both of which are named cholinergic receptors:
    • Nicotinic (N) Cholinergic Receptors
    • Muscarinic (M) cholinergic receptors

Nicotinic Receptor Subtypes

  • Nicotinic Neuronal (Nn):

    • Location: Sympathetic and parasympathetic postganglionic ganglions
    • Function: Difficult to predict given complexity of interactions between both systems
    • Location: Adrenal glands (medulla)
    • Function: Adrenaline and noradrenaline (4:1 ratio) released as hormones in the bloodstream

  • Nicotinic Muscular (Nm):

    • Location: Skeletal muscles (Somatic system)
    • Function: Skeletal muscle depolarization and contraction; overstimulation leads to paralysis

Muscarinic Receptor Subtypes

  • M1, M4, M5:

    • Location: Brain
    • Function: Variety of effects according to the neuronal pathway implicated

  • M2:

    • Location: Heart muscle
    • Function: Decreased heart rate, decreased force of contraction (atria)

  • M3:

    • Location: Smooth muscle, glands (salivary, lacrimal, bronchial, GI)
    • Function: Stimulation of parasympathetic effects
    • Location: Eyes (Iris sphincter)
    • Function: Contraction (miosis)
    • Location: Eyes (Ciliary muscle)
    • Function: Contraction (accommodation)
    • Location: Sweat glands (sympathetic system)
    • Function: Diaphoresis

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