Synaptic Transmission

Question 1

How can dietary intake affect neurotransmitter synthesis?

Answer 1

Neurotransmitter synthesis takes place inside the neuron and requires transport of specific precursor molecules across the plasma membrane.

Dietary intake of certain amino acids can influence precursor availability. Example: tryptophan. A diet low in tryptophan combined with high intake of amino acids that are taken up by the same amino acid transporter that takes up tryptophan can reduce serotonin production.

Question 2

How can therapeutic drugs affect neurotransmitter synthesis?

Answer 2

can inhibit enzymes involved in neurotransmitter production

Question 3

Give an example of precursor loading and the effect this can have on neurotransmission.

Answer 3

Precursor loading can increase neurotransmission Ex: L DOPA in Parkinson’s Disease

Question 4

All neurotransmitters are stored in secretory vesicles. What are the exceptions?

Answer 4

gases and some nucleosides are not stored in secretory vesicles

Question 5

What happens when vesicular transport is inhibited?

Answer 5

Neurotransmitters in the cytoplasm can be degraded
when vesicular transport is inhibited resulting in
neurotransmitter depletion.

(Storage of neurotransmitters in synaptic vesicles protects them from degradation by cytosolic enzymes. Packaging of protein neurotransmitters in large vesicles at the cell body enables the transport of protein
neurotransmitters down the axon to the nerve terminal.)

Question 6

Describe the mechanism and effect of Botulinum toxin. For what use might it be prescribed clinically?

Answer 6

Botulinum toxin is endocytosed into cholinergic neurons and degrades SNAREs of the cholinergic neuromuscular junction resulting in skeletal muscle paralysis due to loss of acetylcholine release. (Prevents calcium-dependent exocytosis of neurotransmitter).

Botulinum toxin is now used therapeutically to treat localized muscle spasms.

Question 7

What is the effect of tetanus toxins? Give a clinical example.

Answer 7

targets neurons that inhibit motor neurons resulting in excessive muscle tone.

This occurs first in the masseter muscle resulting in “lockjaw”.

Question 8

Describe the mechanism and indication of amphetamine or ephedrine.

Answer 8

indirectly acting drug (does not interact directly with a receptor) that stimulates release of neurotransmitters in a Ca-independent manner

Amphetamine is taken up by re-uptake transporters at the axon terminal and once inside the cell, can activate signaling mechanisms that actually reverse the direction of neurotransmitter transport, resulting in the release of endogenous neurotransmitter back out to the extracellular side of the membrane without any membrane voltage change and Ca influx

Indication: Analgesia in surgery
Mechanism: Reverse monoamine reuptake transporters

Question 9

What is the effect of drugs that act on pre-synaptic receptors? Give an example.

Answer 9

Drugs can act on pre-synaptic
receptors to modulate neurotransmitter
release by altering the influx of calcium following action potential generation.

Contributes to some side
effects, e.g., adrenergic receptor agonists used for asthma cause muscle
tremor by stimulating acetylcholine release from motor neurons.

Question 10

Where can re-uptake of the neurotransmitter out of synaptic cleft occur?

Answer 10

pre-synaptic nerve terminal
post-synaptic cell
surrounding glial cells

(primary reuptake site is dependent on the location of reuptake protein expression

Question 11

What are the three major mechanisms that account for termination of neurotransmitter action?

Answer 11

Re-uptake of the nt out of synaptic cleft at pre-synaptic nerve terminal, post synaptic cell or surrounding glial cells

diffusion out of the synaptic cleft

metabolic transformation and degradation

Question 12

How is the action of the following terminated:

Monoamines (serotonin, norepinephrine, dopamine)

Acetylcholine

Answer 12

Monoamines - terminated by re-uptake into the pre-synaptic cell

Acetylcholine - degraded in synaptic cleft

Question 13

Describe the action and effect of metyrosine.

What is its indication?

Answer 13

binds to tyrosine hydroxylase (the enzyme that catalyzes the RLS in production of catecholamines), but cannot be transformed to DOPA, so decreases production of dopamine

Metyrosine is used in the treatment of hypertension by reducing norepinephrine production

Indication: Hypertension

Mechanism of action: Competitive inhibition of tyrosine hydroxylase

Question 14

Describe L-DOPA. What is it used to treat? What are some side effects?

Indication/Mechanism?

Answer 14

precursor of dopamine

used to treat Parkinson’s disease in which dopaminergic neurons in the brain are damaged

Since DOPA and dopamine
are also precursors of norepinephrine. DOPA loading can have adverse effects on
the cardiovascular system due to enhanced norepinephrine neurotransmission in the
peripheral autonomic nerves.

Indication: Parkinson’s disease
Mechanism: precursor of dopamine, stimulates dopamine production

Question 15

Describe the mechanism and effect of Carbidopa.

Indications?

Answer 15

blocks conversion of L DOPA to dopamine

Carbidopa does not cross the BBB

Can be used to reduce the CV effects of L-DOPA in peripheral adrenergic nerves, and preserve the beneficial effects of L-DOPA treatment for Parkinson’s disease within the CNS

Indication: Parkinson’s

Mechanism: Blocks L-DOPA conversion to
dopamine, does not cross BBB, so protects peripheral adrenergic
neurons from producing too much dopamine and norepinephrine

Question 16

What are the monoamines?

Answer 16

serotonin, norepinephrine, histamine, dopamine

Question 17

Describe the synthesis of NE. Where does it take place? What enzyme is involved?

Answer 17

Dopamine is transformed to norepinephrine by dopamine B-hydroxylase. The doapmine B-hydroxylase enzyme is expressed within the vesicle. This prevents the destruction of NE in the cytosol where oxidative enzymes rapidly degrade it

Question 18

What is the mechanism of action of Reserpine? Indications? Side effects?

Answer 18

The vesicular monoamine
transporter (VMAT) is
blocked by reserpine which results in the depletion of monoamines (NE, DA, and serotonin).

Reserpine can cross the blood brain barrier and block monoamine vesicular uptake in CNS neurons which can contribute to depression. Reserpine is now used safely and effectively at low doses that are combined with other antihypertensive drugs
to treat refractory hypertension.

Indication: Hypertension
Mechanism: Inhibits VMAT uptake of monoamines

Question 19

What is the mechanism and effects of Bretylium?

What is it indication?

Will it affect cholinergic or adrenergic neurotransmission?

Answer 19

inhibits excitability of the
nerve terminal membrane and Ca2+-dependent fusion of the synaptic vesicle with the pre-synaptic plasma membrane thusb reducing neurotransmitter release.

Bretylium has affinity for, and is taken up by reuptake transporters proteins that normally take up norepinephrine. Thus bretylium has specific effects on adrenergic neurotransmission.

This drug is used to reduce ventricular arrhythmia in a hospital setting.

Indication: Ventricular arrythmia

Action: Inhibit action potential generation and Ca dep synaptic vesicle fusion

Question 20

What effect will the binding of pre-synaptic alpha or beta adrenergic receptors have on neurotransmitter release?

Answer 20

NE binds to 2 major types of receptors (alpha and beta adrenergic); agonists and antagonists of these receptors used in treatment of CV and respiratory diseases and mood disorders;

Activation of pre-synaptic adrenergic receptors on nerve terminals influences neurotransmitter release, alpha adrenergic receptors can inhibit, while beta-adrenergic receptors can facilitate neurotransmitter release

Question 21

How is the termination of exogenously administered norepinephrine mediated?

Answer 21

mostly by metabolism in the plasma by COMT

(whereas NE released from noradrenergic nerve terminals is mediated primarily by re-uptake and to a lesser degree by diffusion and metabolic transformation)

Question 22

What is MAO?

Answer 22

metabolic enzyme,
monoamine oxidase (MAO), is present within the cell cytoplasm and rapidly oxidizes any norepinephrine and dopamine within the cytoplasm that is not transported into synaptic vesicles within time

Question 23

What the primary mode of terminating monoamine actions?

Answer 23

re-uptake

Question 24

What is the mechanism and indication of cocaine?

Answer 24

Cocaine inhibits re-uptake of monoamines including norepinephrine, dopamine and serotonin

Indication: analgesia in surgery
Mechanism: blocks monoamine reuptake

Question 25

Differentiate between tri-cyclic antidepressants and SSRIs.

Indication? Mechanism?

Answer 25

Tri-cyclic antidepressants block re-uptake of several monoamines. As the name implies selective serotonin re-uptake inhibitors (SSRIs) provide a more selective inhibition of serotonin reuptake from the synapse of serotonergic neurons.

Indication SSRI: depression/anxiety

Mechanism: selective inhibition of serotonin reuptake transporter

Question 26

What can be a side effect of antidepressants?

Answer 26

they have to cross BBB to mediate their effects; they can also have significant side effects particularly in the CV system which is richly innervated by noradrenergic neurons

Question 27

Where do COMT and MAO metabolize NE?

Answer 27

COMT- plasma

MAO- within the cell cytoplasm (rapidly oxidizes any NE and D within cytoplasm that is not transported into synaptic vesicles within time)

Question 28

Metabolism is less important for termination of endogenously released catecholamine since re-uptake from the synapse is so efficient.

What about circulating catecholamines such as those released by the adrenal gland or those administered exogenously?

Answer 28

Circulating catecholamines such as those released by the adrenal gland or those
administered exogenously are subject to metabolism by COMT.

The efficiency of this enzyme dramatically reduces the half-life of exogenously administered catecholamines.

Question 29

What is the action of phenylephrine? Indication?

Answer 29

synthetic drug designed to activate adrenergic receptors that is
resistant to degradation by COMT and so has a longer half-life.

Indication: hypotension during surgery
Action: Direct agonist of adrenergic receptor

Question 30

What effect will MAO inhibitors have?

Indication/Mechanism?

Answer 30

Metabolism becomes a factor for catecholamines that have been taken
back up into the cell. If they are not rapidly transported into the synaptic vesicle they become subject to rapid degradation by monoamine oxidase (MAO). MAO inhibitors lead to increased catecholamines in the cytoplasm.

As norepinephrine accumulates in the cytoplasm, the transporter protein reverses direction
leading to expulsion of norepinephrine into the synapse.

Indication: depression
Mechanism: blockade of cytoplasmic metabolism of monoamines

Question 31

What effect can ingested tyramine have in the presence of MAO inhibitors?

Indications/Mechanism?

Answer 31

tyramine can be taken up into noradrenergic cells.

However, ingested tyramine is normally subject to significant first pass metabolism by MAO’s in the liver.

When MAOs are inhibited, such as during treatment for depression, ingested tyramine accumulates and is transported into adrenergic cells where it competes with norepinephrine for transport into synaptic vesicles resulting in even
higher levels of cytoplasmic norepinephrine than with MAO inhibitors alone.

The cytoplasmic
accumulation of norepinephrine can reverse the concentration gradient across the plasma membrane and cause the reversal of the reuptake transporter. The resulting excessive release of norepinephrine can lead to a hypertensive crisis due to excessive vasoconstriction by norepinephrine in the periphery

Older MAOIs were irreversible and non-selective (block both MAO-A and MAOB). Newer selective drugs can block MAO-A leaving MAO-B intact, allowing for tyramine degradation in gut, but still provides inhibition of serotonin, NE and DA breakdown in brain.

Indications: Ingested in diet, not therapeutic

Mechanism: competes w NE for transport into synaptic vesicle

Question 32

Describe the process of neuropeptide synthesis and how it differs from other neurotransmitters.

Answer 32

Neuropeptide synthesis
requires the production of specific mRNAs within the nucleus.

The mRNAs are transported from the nucleus and translated into prepropeptide in the rough endoplasmic reticulum.

Various cleavage processes mediated by peptidases ensue that lead to the production of active neuropeptide.

Question 33

Describe how neuropeptide storage differs from other neurotransmitters.

Answer 33

in contrast to
other neurotransmitters, the neuropeptides are packaged into large “dense core vesicles”.

This packaging occurs at the endoplasmic reticulum and so is difficult to target selectively.

The vesicles are transported to the nerve terminal.

Question 34

In order to stimulate peptide release, are longer or shorter duration intracellular calcium concentrations required?

Answer 34

Dense core vesicles reside farther away from the pre-synaptic membrane than do small synaptic vesicles.

Consequently, increases in intracellular calcium
concentration of longer duration are required to stimulate peptide release.

Neuropeptides are often produced within other neuronal types and are co-released when the nerve terminal is activated.

Question 35

What effect will bretylium have on neuropeptide release? Explain.

Answer 35

Neuropeptides are often produced within other neuronal types and are co-released when the nerve terminal is activated.

Therefore, drugs that target membrane ion
channels to influence release of classic neurotransmitters, e.g., bretylium, will also
influence neuropeptide release as well.

Question 36

How does binding of neurotransmitter to receptor differ with peptide neurotransmitters?

How does this affect the production/action of peptidergic analogs?

Answer 36

peptide neurotransmitters travel much farther distances
to reach their receptor than do other neurotransmitters. Peptide molecules are also
much larger than other classic neurotransmitters

peptidergic analogs have been developed for pharmaceutical use.
However, they are unsuitable for use in the modification of neurotransmission in the
CNS because they cannot cross the blood brain barrier.

many nonpeptidergic
receptor agonists and antagonists have been developed to allow for
penetration into the CNS

Question 37

Describe Naloxone. What type of drug? Explain its action and mechanism.

Compare to Naltrexone.

Answer 37

Naloxone is a non-peptide opioid receptor antagonists

Naloxone is a small lipophilic molecule widely used to reverse opioid overdose

Naltrexone has a longer duration of action and is used in the treatment of opiate addiction and alcoholism.

Indication: opioid overdose or dependence

Mechanism: non-peptide blockers of opioid receptors in CNS

Question 38

How is the action of neuropeptides terminated? How does this differ from other neurotransmitters.

Answer 38

Neuropeptides are not taken up into the nerve terminal.

The major mechanism of neuropeptide inactivation is by cleaving via peptidases.

However, peptidases usually have multiple targets, therefore, their inhibition can lead to side
effects.

As yet, peptidases have not been a major target of pharmacotherapy of
neurotransmission though this is an active area of pharmaceutical research.

Question 39

ACE inhibitors e.g. lisinopril

Indications/Mechanism

Answer 39

Indications: hypertension

inhibits peptide cleavage of Angiotensin I to Angiotensin II