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