Synaptic Transmission Flashcards
How can dietary intake affect neurotransmitter synthesis?
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.
How can therapeutic drugs affect neurotransmitter synthesis?
can inhibit enzymes involved in neurotransmitter production
Give an example of precursor loading and the effect this can have on neurotransmission.
Precursor loading can increase neurotransmission Ex: L DOPA in Parkinson’s Disease
All neurotransmitters are stored in secretory vesicles. What are the exceptions?
gases and some nucleosides are not stored in secretory vesicles
What happens when vesicular transport is inhibited?
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.)
Describe the mechanism and effect of Botulinum toxin. For what use might it be prescribed clinically?
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.
What is the effect of tetanus toxins? Give a clinical example.
targets neurons that inhibit motor neurons resulting in excessive muscle tone.
This occurs first in the masseter muscle resulting in “lockjaw”.
Describe the mechanism and indication of amphetamine or ephedrine.
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
What is the effect of drugs that act on pre-synaptic receptors? Give an example.
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.
Where can re-uptake of the neurotransmitter out of synaptic cleft occur?
pre-synaptic nerve terminal
post-synaptic cell
surrounding glial cells
(primary reuptake site is dependent on the location of reuptake protein expression
What are the three major mechanisms that account for termination of neurotransmitter action?
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
How is the action of the following terminated:
Monoamines (serotonin, norepinephrine, dopamine)
Acetylcholine
Monoamines - terminated by re-uptake into the pre-synaptic cell
Acetylcholine - degraded in synaptic cleft
Describe the action and effect of metyrosine.
What is its indication?
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
Describe L-DOPA. What is it used to treat? What are some side effects?
Indication/Mechanism?
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
Describe the mechanism and effect of Carbidopa.
Indications?
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
What are the monoamines?
serotonin, norepinephrine, histamine, dopamine
Describe the synthesis of NE. Where does it take place? What enzyme is involved?
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
What is the mechanism of action of Reserpine? Indications? Side effects?
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
What is the mechanism and effects of Bretylium?
What is it indication?
Will it affect cholinergic or adrenergic neurotransmission?
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
What effect will the binding of pre-synaptic alpha or beta adrenergic receptors have on neurotransmitter release?
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
How is the termination of exogenously administered norepinephrine mediated?
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)
What is MAO?
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
What the primary mode of terminating monoamine actions?
re-uptake
What is the mechanism and indication of cocaine?
Cocaine inhibits re-uptake of monoamines including norepinephrine, dopamine and serotonin
Indication: analgesia in surgery
Mechanism: blocks monoamine reuptake
Differentiate between tri-cyclic antidepressants and SSRIs.
Indication? Mechanism?
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
What can be a side effect of antidepressants?
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
Where do COMT and MAO metabolize NE?
COMT- plasma
MAO- within the cell cytoplasm (rapidly oxidizes any NE and D within cytoplasm that is not transported into synaptic vesicles within time)
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?
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.
What is the action of phenylephrine? Indication?
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
What effect will MAO inhibitors have?
Indication/Mechanism?
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
What effect can ingested tyramine have in the presence of MAO inhibitors?
Indications/Mechanism?
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
Describe the process of neuropeptide synthesis and how it differs from other neurotransmitters.
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.
Describe how neuropeptide storage differs from other neurotransmitters.
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.
In order to stimulate peptide release, are longer or shorter duration intracellular calcium concentrations required?
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.
What effect will bretylium have on neuropeptide release? Explain.
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.
How does binding of neurotransmitter to receptor differ with peptide neurotransmitters?
How does this affect the production/action of peptidergic analogs?
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
Describe Naloxone. What type of drug? Explain its action and mechanism.
Compare to Naltrexone.
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
How is the action of neuropeptides terminated? How does this differ from other neurotransmitters.
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.
ACE inhibitors e.g. lisinopril
Indications/Mechanism
Indications: hypertension
inhibits peptide cleavage of Angiotensin I to Angiotensin II
