L13 concepts

Question 1

5 steps in Neurotransmission

Answer 1

1. NT synthesis
2. Vesicular Storage
3. Synaptic Release
4. Binding to receptor
5. Termination of transmission

Question 2

Requirements for NT synethesis

Answer 2

precursors
transport into the cell
enzymatic action

Question 3

Thing that can affect NT synethesis

Answer 3

1. therapeutic drugs can inhibit enzymes involved
2. dietary intake of certain amino acids can influence availability (low tryptophan intake can reduce serotonin)
3. Precursor loading- can increase neurotransmission (L-DOPA in parkinson’s disease)

Question 4

which NT’s are stored in vesicles?

Answer 4

All except gases and some nucleosides

Question 5

What are the benefits to storing NTs in vesicles

Answer 5

protects them from degradation by cytosolic enzymes and concentrates them for release (if storage transporters are inhibited then NTs get degraded)

Question 6

Synaptic Release

Answer 6

Depolarization of the nerve terminal > Ca channels open and Ca influx > SNARE proteins on the vessel interact with SNARE proteins on the membrane > rapid release of NTs

Question 7

Boxulinum toxin

Answer 7

degrades SNAREs of the cholinergic neuromuscular junction resulting in skeletal muscle paralysis. Can be used to treat muscle spasms

Endocytosed into cholinergic neurons
Degrades SNARES
Prevents calcium-dependent exocytosis of neurotransmitter

Question 8

amphetamine synaptic release

Answer 8

has affinity for monoamine re-uptake transporters

leads to transporter phosphorylation -which reverses the direct of NT transport

probably also inhibits vesicular uptake proteins

calcium-independent release of neurotransmitter (no voltage change or Ca influx)

Question 9

SNARES

Answer 9

Enable calcium-dependent docking of vesicle with pre-synaptic membrane

Enable exocytosis of neurotransmitter

Question 10

indirect acting drugs

Answer 10

can increase neurotransmission and increase the effects of activating a receptor by stimulating the release of endogenous NT

Question 11

receptor binding

Answer 11

can bind receptors on pre and post synaptic cell membranes

drugs that bind directly to receptors provide the most selective manipulation of synaptic transmission

drugs acting on pre-synaptic receptors to modulate NT release can contribute to some side effects

Question 12

3 mechanisms for Termination of NT action

Answer 12

1. reuptake (can occur at the pre-synaptic nerve terminal, the post-synaptic cell or the surrounding glial cells depending on the location of the reuptake protein)
2. Diffusion (out of the synaptic cleft)
3. Metabolic transformation and degradation

Question 13

Dopamine is made from what precursor and by what enzyme?

Answer 13

Tyrosine via tyrosine hydroxylase

Question 14

Dopamine is a precursor to what molecules

Answer 14

norepinephrine and epinephrine

Question 15

how is epinephrine formed

Answer 15

tyrosine > DOPA > dopamine > norepinephrine > epinephrine

Question 16

rate limiting step in catecholamine production

Answer 16

Hydroxylation of tyrosine by tyrosine hydroxylase

Question 17

Metyrosine

Answer 17

binds tyrosine hydroxylase but cannot be transformed to DOPA, decreasing dopamine production. Used for hypertension bc it decreases the NE produced

Question 18

L-DOPA

Answer 18

a precursor to dopamine. Used to treat Parkinson’s disease but increasing the amount of dopamine.

DOPA loading can have adverse effects of the CV system due to increased NE in the peripheral autonomic nerves

Question 19

carbidopa

Answer 19

blocks the conversion of L-DOPA to dopamine.

does not cross the BBB. Can be used to decrease the cardiovascular side effects of L-DOPA in peripheral adrenergic nerves

Question 20

B-hydroxylase what does it do and where is it located?

Answer 20

It transforms dopamine to norepinephrine. It is located within the vesicle so that the NE is not degraded by cytosolic enzymes

Question 21

Vesicular monoamine transporter (VMAT)

Answer 21

is responsible for transporting dopamine into synaptic vesicles. Is specific to monamines (serotonin, NE, histamine, and dopamine)

Question 22

reserpine

Answer 22

blocks VMAT resulting in depletion of monoamines (NE, DA, and serotonin).

can cross the BBB and block monoamine vesicular uptake in the CNA neurons contributing to depression

used at low doses to treat hypertension

Question 23

Bretylium

Answer 23

inhibits excitability of the nerve terminal membrane and reduces neurotransmitter release.

affects adrenergic neurotransmission ( taken up by transporters that normally take up NE)

reduces ventricular arrhythmias

Question 24

primary mode of terminating monoamine actions

Answer 24

reuptake

Question 25

catecholamine-O-methyltransferase (COMT)

Answer 25

an enzyme in the plasma that inactivates NE by metabolism. The main termination of exogenously administered NE. metabolizes circulating monomaines (exogenous and released by the adrenal gland)

Question 26

Monamine Oxidase (MAO)

Answer 26

oxidizes norepinephrine and dopamine within the cytoplasm that is not transported into vesicles fast enough

Question 27

cocaine

Answer 27

inhibits re-uptake of monoamines including NE, dopamine and serotonin

Question 28

Common mechanism of drugs used to treat depression and anxiety

Answer 28

blocking/inhibiting monoamine reuptake must be able to cross the BBB can have significant systemic side effects (particularly CV which is richly innervated by noradrenergic neurons)

Question 29

phenylephrine

Answer 29

drug that was developed to be resistant to COMT degradation and therefore has a longer half-life activates adrenergic receptors

Question 30

MAO inhibitors

Answer 30

lead to increased catecholamines in the cytoplasm. As NE accumulates in the cytoplasm the transporter protein reverses direction leading to expulsion of NE into the synapse.

Question 31

Tyramine

Answer 31

comes form a dietary source. normally has first pass metabolism by MAOs in the liver. when MAOs are inhibited- tyramine accumulates and is transported into adrenergic cells where it competes with NE for transport into synaptic vesicles resulting in even higher level of cytoplasmic NE than with MAO inhibitors alone. Reversal of the reuptake transporter can then lead to a hypertensive crisis

Question 32

neuropeptides

Answer 32

required longer increases in Ca to stimulate peptide release (bc they must travel further) and often produced within other neuronal types and are co-released when the nerve terminal is activated. therefore drugs that target membrane ion channels also affect neuropeptides (bertylium)

Question 33

challenge for making peptigergic analogs

Answer 33

the are large and we don't fully understand how they interact with their receptors and the cannot cross the BBB therefore many non-peptidergic receptor agonist and antagonist have been developed for penetration into the CNS

Question 34

naloxone

Answer 34

small lipophilic molecule used to reverse opioid overdose.

Question 35

naltrexone

Answer 35

longer duration of action than naloxone and is used in the treatment of opiate addiction and alcoholism

Question 36

ways neuropeptides differ from classical | neurotransmission

Answer 36

Requires mRNA for synthesis Peptidases required to make final neurotransmitter* Stored in “large dense core vesicles” Made in soma and transported Stored away from synapse, and requires longer stimulus for release Travel farther to bind receptor* Non-specific peptidase-induced metabolism