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Serotonin Flashcards

1
Q

What type of neurotransmitter is Serotonin?

A

Monoamine neurotransmitter alongside Noradrenaline and Dopamine.

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2
Q

Where is 5-HT found?

A

In the gut
In platelets and has a role in platelet aggregation
In the CNS

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3
Q

Describe the synthesis pathway of Serotonin.

A

Serotonin is derived from the precursor Tryptophan which is derived from our diet. Tryptophan is converted by two enzymes within the cascade to Serotonin. The first Tryptophan hydroxylase converts it to 5-hydroxytryptophan before being converted by L-aromatic acid decarboxylase (also known as dopa decarboxylase or 5-Hydroxytryptophan decarboxylase) to 5-Hydroxytryptamine (Serotonin). The neurotransmitter is then packaged into synaptic vesicles and used.

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4
Q

Describe the metabolism of Serotonin.

A

Monoamine oxidase present intercellularly is responsible for the degradation of 5-Hydroxytryptamine (Serotonin) into an intermediate which is then further metabolised by aldehyde dehydrogenase into 5-Hydroxyindoleacetic acid which is then excreted.

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5
Q

Describe the process of serotonergic neurotransmission.

A

Within the nerve terminal, tyrpothophan is broken down into 5-Hydroxytryptamine (Serotonin). Vesicular monoamine transporter (VMAT) facilitates the loading of Serotonin into synaptic vesicles. Similar to the release of other neurotransmitters, depolarisation of the pre-synaptic terminal leads to an increase in Ca2+ permeability. Calcium ion influx then facilitates Ca2+ dependent exocytosis controlling the release of 5-HT into the synaptic cleft. Serotonin is then able to act on their post-synaptic receptors.

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6
Q

How does Serotonin re-uptake occur?

A

The reuptake of Serotonin from the synaptic cleft to the pre-synaptic serotonergic neuron is facilitated by the presence of the monoamine transporter protein SERT encoded by the SLC6A4 gene. Also known as sodium-dependent serotonin transporter it is a 12 transmembrane domain symporter that relies on the presence of sodium as a co-transporter ion.

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7
Q

What are serotonergic neurons?

A

Any neuron that uses 5-HT (Serotonin) as a neurotransmitter.

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8
Q

Where are serotonergic neurons specifically found?

A

Their cell bodies lie within the Ralphe nucleus and are able to project to different areas within the brain.
They have a similar distribution to noradrenergic neurons.

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9
Q

Which physiological processes is 5-HT involved in?

A

Sleep
Appetite
Pain
Thermoregulation
Mood

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10
Q

What type of receptors are Serotonin receptors?

A

14 known 5-HT receptors and all but one are GPCR.
5-HT3 is a ligand gated ion channel

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11
Q

What are the seven different types of Serotonin receptor?

A

Seven different types:
◦ 5-HT1 receptors (1A, 1B, 1D, 1E, 1F)
◦ 5-HT2 receptors (2A, 2B, 2C)

◦ 5-HT4, 5-HT5A, 5-HT6 and 5-HT7
receptors

Categorised based on the G-protein they couple to and their downstream signalling response.

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12
Q

What is the signalling pathways for 5-HT1 receptors?

A

As all 5-HT1 receptors (1A, 1B, 1D, 1E, 1F) are GPCRs they all couple to the inhibitory G protein Gi/G0 which when activated, inactivates adenylyl cyclase, decreasing cyclic AMP levels and may modulate calcium channels. This results in an overall inhibitory effect.
Specifically 5-HT1A when activated initiates a downstream signalling cascade which causes neuronal inhibition whereas 5-HT1B causes presynaptic inhibition.

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13
Q

Where is 5-HT1A located?

A

Chiefly in the CNS

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14
Q

Where is 5-HT1B located?

A

CNS
Vascular smooth muscle

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15
Q

Where is 5-HT1D located?

A

CNS
Blood vessels

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16
Q

Where is 5-HT1E located?

A

CNS

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17
Q

Where is 5-HT1F located?

A

CNS
Uterus
Heart
GI tract

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18
Q

What is the signalling pathways for 5-HT2 receptors?

A

As all 5-HT2 receptors (2A, 2B, 2C) are GPCRs they all couple to the G-protein Gaq/11 to regulate the activity of phospholipase C resulting in an increase in IP3 and Ca2+ causing neuronal excitation.
5-HT2A specifically when activated initiates a downstream signalling pathway which leads to neuronal excitation as it is expressed in the CNS.

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19
Q

Where is 5-HT2A located?

A

CNS
PNS
Smooth muscle
Platelets

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20
Q

Where is 5-HT2B located?

A

Gastric fundus

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21
Q

Where is 5-HT2C located?

A

CNS
Lymphocytes

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22
Q

Describe the signalling pathway of 5-HT3A.

A

As a ligand gated ion channel which is cation selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems.
The 5-HT3 receptor consists of 5 subunits centralised around the central ion conducting pore and is permeable to sodium, potassium and calcium ions. Upon serotonin binding the pore opens and there is an inward current of sodium and potassium ions resulting in neuronal excitation (maybe due to depolarisation which then increase permeability to calcium inducing Ca2+ dependent exocytosis of neurotransmitters).

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23
Q

Where is 5-HT3A located?

A

CNS
PNS

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24
Q

Describe the signalling pathway of 5-HT4, 5A, 6 and 7.

A

All couple to Gas which upon activation, activates adenylyl cyclase in turn increasing levels of cAMP causing neuronal excitation.

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25
Q

Where is 5-HT4 located?

A

PNS (GI)
CNS

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26
Q

Where is 5-HT5A located?

A

CNS

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27
Q

Where is 5-HT6 located?

A

CNS
Leukocytes

28
Q

Where is 5-HT7 located?

A

CNS
GI
Blood vessels

29
Q

Describe the purpose of using 5-HT2 antagonists for migraine prophylaxis.

A

5-HT2 causes neuronal excitation, smooth muscle contraction by inducing activation of phospholipase C and increasing intercellular calcium and vasoconstriction. This vasoconstriction occurs during migraines due to release of Serotonin, with rebound vasodilation causing throbbing headaches.

30
Q

Which drug targets 5-HT3 receptor?

A

Ondansteron which is a 5-HT3 antagonist. 5-HT3 receptors are expressed mostly highly on the solitary tract nucleus (STN) and the chemoreceptor trigger zone (CTZ). Therefore by Ondansetron antagonising receptors on neurons found in the chemoreceptor trigger zone this provides relief of nausea and vomiting. Ondansetron is highly used in chemotherapy induced nausea and vomiting.

31
Q

Which agonists act at 5HT1A receptor?

A

8-OH-DPAT, triptans, clozapine,
buspirone (PA), cabergoline

32
Q

Which antagonists act at 5HT1A receptor?

A

Methiothepin, yohimbine,
ketanserin, pizotifen, spiperone

33
Q

Which agonists act at 5HT1B receptor?

A

8-OH-DPAT, triptans (PA),
clozapine, cabergoline,
dihydroergotamine

34
Q

Which antagonists act at 5HT1B receptor?

A

Methiothepin (IA), yohimbine,
ketanserin, spiperone

35
Q

Which agonists act at 5HT1D receptor?

A

8-OH-DPAT, triptans, clozapine, cabergoline (PA), dihydroergotamine/ ergotamine

36
Q

Which antagonists act at 5HT1D receptor?

A

Methiothepin (IA), yohimbine, ketanserin, methysergide, spiperone

37
Q

Which agonists act at 5HT1E receptor?

A

8-OH-DPAT, triptans; clozapine,
dihydroergotamine

38
Q

Which antagonists act at 5HT1E receptor?

A

Methiothepin, yohimbine,
methysergide

39
Q

Which agonists act at 5HT1F receptor?

A

8-OH-DPAT, triptans; clozapine
dihydroergotamine/ ergotamine,
lamistidan

40
Q

Which antagonists act at 5HT1F receptor?

A

Yohimbine, methysergide

41
Q

Which agonists act at 5HT2A receptor?

A

LSD, cabergoline, methysergide
(PA), 8-OH-DPAT, ergotamine (PA)

42
Q

Which antagonists act at 5HT2A receptor?

A

Ketanserin, clozapine,
methysergide

43
Q

Which agonists act at 5HT2B receptor?

A

LSD, cabergoline, methysergide
(PA), 8-OH-DPAT, ergotamine (PA)

44
Q

Which antagonists act at 5HT2B receptor?

A

Ketanserin, clozapine, yohimbine

45
Q

Which agonists act at 5HT2C receptor?

A

LSD, cabergoline, methysergide
(PA), 8-OH-DPAT, ergotamine (PA)

46
Q

Which antagonists act at 5HT2C receptor?

A

Ketanserin, clozapine (IA),
methysergide

47
Q

Which agonists act at 5HT3 receptor?

A

2-Me-5-HT,
chloromethyl biguanide

48
Q

Which antagonists act at 5HT3 receptor?

A

Granisetron, ondansetron,
palonosetron.

49
Q

Which agonists act at 5HT4 receptor?

A

Metoclopramide, tegaserod (PA),
cisapride

50
Q

Which antagonists act at 5HT4 receptor?

A

Tropisetron

51
Q

Which agonists act at 5HT5A receptor?

A

Triptans, 8-OH-DPAT

52
Q

Which antagonists act at 5HT5A receptor?

A

Clozapine, methysergide, yohimbine, ketanserin

53
Q

Which agonists act at 5HT6 receptor?

A

LSD, ergotamine

54
Q

Which antagonists act at 5HT6 receptor?

A

Clozapine (IA), spiperone, methysergide, dihydroergotamine

55
Q

Which agonists act at 5HT7 receptor?

A

Buspirone (PA), bromocriptine,
cisapride, 8-OH-DPAT, LSD,

56
Q

Which antagonists act at 5HT7 receptor?

A

Clozapine (IA), methysergide,
buspirone, dihydroergotamine,
ketanserin, yohimbine

57
Q

What are the clinical effects mediated by 5-HT1A?

A

Behavioural effects: sleeping, feeding, thermoregulation and anxiety

58
Q

What are the clinical effects mediated by 5-HT1B?

A

Behavioural effects, pulmonary vasoconstriction

59
Q

What are the clinical effects mediated by 5-HT1D?

A

Cerebral vasoconstriction
Locomotion

60
Q

What are the clinical effects mediated by 5-HT2A?

A

Behavioural effects
Platelet aggregation
Smooth muscle contraction
Vasoconstriction/Vasodilation

61
Q

What are the clinical effects mediated by 5-HT2B?

A

Contraction

62
Q

What are the clinical effects mediated by 5-HT3?

A

Emesis (anti-emetic use)
Behavioural effects (anxiety)

63
Q

What are the clinical effects mediated by 5-HT4?

A

GI motility

64
Q

What are the clinical effects mediated by 5-HT5A?

A

Modulation of exploratory behaviour

65
Q

What are the clinical effects mediated by 5-HT6?

A

Learning and memory
Modulation of neurotransmission

66
Q

What are the clinical effects mediated by 5-HT7?

A

Thermoregulation
Circadian rhythm

Central Nervous System (11 decks)

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