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Flashcards in CAL 3 Deck (98)
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1
Q

What is 5HT

A

5-HT (5-hydroxytryptamine, serotonin) is an indolealkylamine neurotransmitter with an uneven distribution in the CNS.

2
Q

what are the hallucinogenic effects of LSD due to

A

The hallucinogenic effects of LSD (lysergic acid diethylamide) are due to a direct interaction with brain 5-HT systems

3
Q

what molecules is 5HT made out of

A
  • carbon
  • oxygen
  • hydrogen
  • nitrogen
4
Q

what 5 steps does the transmission of 5HT involve

A
  1. Synthesis
  2. Storage
  3. Release
  4. Activation of 5-HT receptors
  5. Inactivation of 5-HT
5
Q

describe how the synthesis of 5HT happens

A
  • trytopathan is actively taken up into the nerve terminal
  • it uses a large amino acid carrier therefore is subjected to competitive inhibition by amino acids such as valine and leucine
  • trytoptophan is converted to 5HTP by trytoptophan hydroxylase
  • 5HTP is then converted to 5HT via DOPA decarboxylase (also known as L aromatic decarboxylase)
6
Q

describe how the storage of 5HT happens

A

Presynaptic vesicles.
- 5-HT is stored in vesicles, together with specific proteins. - Vesicles are recycled, so that once the transmitter has been released they can be refilled with newly- synthesised transmitter (and also with re-captured transmitter) and the cycle of release is repeated.

7
Q

describe how 5HT is put into vesicles

A
  • a carrier molecule couples 5HT with sodium in an ATPase dependent process
  • this is because it is going against the concentration gradient
8
Q

how many families are there of 5HT post synaptic receptors

A

7

9
Q

describe how 5HT is inactivated

A
  • 5HT goes back to the vesicles and is stored in them
  • MAO degrades 5HT and turns it back to 5HTP
  • 5HTP is then oxidsed to 5-HIAA
10
Q

Where are the cell bodies of 5-HT neurones located

A

The cell bodies of 5-HT neurones are primarily located in the raphe nuclei which are located in the pons and upper brainstem.

11
Q

what are the two subgroups of 5HT neurone cell bodies

A
  1. Caudal raphe nuclei

2. Rostral raphe nuclei

12
Q

why is it difficult to asign specific roles to the group of 5HT fibres

A

Because there is widespread overlap of the projection fields of many of the nuclei it is often difficult to ascribe specific roles to many of the groups of fibres.

13
Q

name some other areas neuronal cell bodies containing 5HT can be found

A

Neuronal cell bodies containing 5-HT are also found at other sites including, e.g. the locus coeruleus, which primarily consists of noradrenaline containing cell bodies.

14
Q

Where is the caudal raphe nuclei found

A

The caudal raphe nuclei are located in the lower brain stem.

15
Q

where is the rostral raphe nuclei found

A

The rostral raphe nuclei are located in the upper brainstem and 5-HT fibres project to forebrain structures.

16
Q

where do 5HT fibres primarily project to

A

The 5-HT fibres primarily project to parts of the medulla and to the dorsal horn of the spinal cord.

17
Q

what pathway provides the most extensive monoaminergic system of the brain

A

5-HT pathways provide the most extensive monoaminergic system of the brain.

18
Q

describe what 5HT neurones are like during the day

A

The neurones have a characteristic pacemaker activity which is high during waking arousal and low during sleep.

19
Q

what happens if 5HT function is altered

A

There may be altered 5-HT function in affective disorders, aggressive states and schizophrenia.

20
Q

What are the subtypes of each of the 7 5HT receptors linked by

A

similarities in terms of sequence homology, presence or absence of introns in the genes, and transduction systems they are associated with.

21
Q

what type of receptors are the 5HT receptors

A

5HT3 - ligand gated

- all others are G protein coupled receptors

22
Q

How many subtypes are there of the 5HT1 receptor family and name them

A

5

  • 5HT1A
  • 5HT1B
  • 5HT1D
  • 5HT1E
  • 5HT1F
23
Q

what are all the 5 subtypes from the 5HT1 receptor family negatively coupled to

A

All five subtypes are negatively coupled to adenylate cyclase by a Gi/o protein.

24
Q

What does the drug sumatriptan do

A

The drug sumatriptan binds to the 5-HT1DB (also known as the 5-HT1B) receptor and also to the 5-HT1D receptor.
- it is an antimigraine drug

25
Q

what do the Gi/O protein coupled to the 5HT1A receptor do

A

The Gi/o protein coupled to 5-HT1A receptors also directly activates some K+ channels to reduce neuronal excitability.

26
Q

Where is 5HT1A found ( subtype from the 5HT1 family) and what do they do

A

High densites in limbic areas (regulation of mood and anxiety) and spinal cord (pain perception).

  • Somatodendritic autoreceptors located on 5-HT neurones in the dorsal raphe nucleus inhibit 5-HT release.
  • Post-synaptic receptors hyperpolarize neuronal membranes by direct activation of K+ conductances by Gi/o.
27
Q

Where is 5HT1B found and what do they do ( subtype from the 5HT1 family)

A

High densities in the striatum, hippocampus, cerebellum and layer IV of the cortex.

There are inhibitory autoreceptors located on 5-HT neurones and inhibitory heteroreceptors located presynaptically on other neurones.

28
Q

Where is 5HT1D found and what do they do ( subtype from the 5HT1 family)

A
  • 2 subtypes - 5-HT1Dα and 5-HT1Dβ.
  • High densities in the olfactory system, striatum, cerebellum and parts on the limbic system.
  • 5-HT1Dβ also known as 5-HT1B receptors are located on cranial blood vessels and are thought to be the target of the anti-migraine drug sumatriptan.
29
Q

where are 5HT1E and 5HT1F found ( subtype from the 5HT1 family)

A
  • Both are found in high densities in the hippocampus and cortex.
  • 5-HT1F receptors also found in other brain areas and in the uterus.
30
Q

what are the 5HT2 subtypes coupled to and what do they do

A
  • All three subtypes are coupled to inositol phosphate turnover to increase formation of diacylglycerol and inositol-1,4,5-triphosphate.
31
Q

what is the classical subtype of 5-HT2 receptor

A

5-HT2A

32
Q

The 5-HT2C receptor corresponds to the……

A

receptor previously known as 5-HT1C.

33
Q

name the subtypes of the 5HT2 receptors

A

5-HT2A
5-HT2B
5-HT2C

34
Q

where is 5HT2A found and what does it do (subtype of 5HT2 receptor)

A
  • widespread distribution with densities in the frontal cortex
  • role in anxiety, depression, and nociceptive transmission
  • In the periphery, it mediates contraction of vascular, tracheal and bronchial smooth muscle, platelet aggregation and increase in capillary permeability.
  • Possible target for prophylaxis of migraine.
35
Q

Where is 5-HT2B found and what does it do (subtype of 5HT2 receptor)

A
  • High levels in the cortex and some limbic structures and several peripheral tissues (gut, heart, kidney and lung).
  • Mediates contractions of the rat fundic strip, a classical preparation for studying 5-HT, and some other GIT smooth muscle.
  • Unknown role in the brain.
36
Q

where is 5-HT2C found and what does it do (subtype of 5HT2 receptor)

A
  • Widespread spinal and supra-spinal distribution.
  • Potential roles include regulation of feeding, locomotion, hormone secretion, depression and anxiety.
  • Also located on the endothelial cells of the choroid plexus where they probably influence the rate of formation of cerebrospinal fluid.
37
Q

What receptor type is the 5HT3 receptor

A

Ligand gated, cation-selective ion channels which mediate membrane depolarization/neuronal excitation.

38
Q

where is the 5HT3 receptor found

A
  • Mediate inhibition of release of a number of CNS transmitters.
  • High densities of post-synaptic receptors in the hippocampus, amygdala, area postrema, and some primary afferent terminals in the dorsal horn of the spinal cord.
  • Peripheral location in the gastrointestinal tract.
39
Q

What does the 5HT3 receptor do

A

roles in emesis and possibly anxiety, neuronal migration and differentiation
- mediates fast excitatory transmission

40
Q

What is the 5HT4 receptor coupled to

A

Positively coupled to adenylate cyclase by Gs.

41
Q

Where is the 5HT4 receptor

A

High levels in limbic structures and the striatum, but role in the CNS unknown.

42
Q

what does the 5HT4 receptor do

A

Mediate excitation in the CNS by reducing K+ and increasing Ca²+ conductances.

In the periphery, they open voltage gated Ca²+ channels, directly relax oesophageal smooth muscle, indirectly contract other GIT smooth muscle (by releasing acetylcholine) and increase cardiac rate and force of contraction.

43
Q

what are the two subtypes of 5HT5 receptors

A

5ht5A

5ht5B

44
Q

what is the role of the 5HT5 receptors

A

Unknown transduction pathway, unknown roles.

45
Q

where is 5ht5A and 5ht5B

A

5-ht5A receptors are found in the cortex, hippocampus and cerebellum.

5-ht5B receptors have a more limited distribution.

Not expressed in the periphery

46
Q

What are 5HT6 AND 5HT7 coupled to

A

Both receptors are positively coupled to adenylate cyclase (coupling to the Gs protein).

47
Q

where are 5HT6 and 5HT7 found

A

No peripheral expression of the 5-HT6 receptor detected; low levels of peripheral expression of the 5-HT7 receptor.

48
Q

what drugs bind to 5HT6 and 5HT7

A

Several antidepressants bind with high affinity to the 5-HT6 receptor.

Several neuroleptics bind with high affinity to the 5-HT7 receptor.

49
Q

why is increasing the intake of L-tryptophan in the diet only have a modest effect

A

Although increasing the intake of L-tryptophan in the diet can increase brain levels of 5-HT, the effect is modest because of the low activity of tryptophan hydroxylase.

50
Q

why was L tryptophan withdrawn

A

The drug was withdrawn because of toxic effects (eosinophilia-myalgia syndrome

51
Q

what was L tryptophan used to treat

A

L-tryptophan used to be given either alone or as add-on therapy in the treatment of depression

52
Q

Why is L tryptophan an essential amino acid

A

L-tryptophan is an essential amino acid which, because of its indole side chain, is highly hydrophobic.

53
Q

What can L tryptophan be oxidised to

A

L-tryptophan is a constituent of proteins and in addition to being the precursor of 5-HT, can also be oxidised to kynurenine.

54
Q

wha does tryptophan hydroxylase require in order to work

A

Tryptophan hydroxylase requires molecular oxygen and reduced tetrahydrobiopterin.

55
Q

What is the rate limiting step of the formation of 5HT

A

The formation of 5-hydroxytryptophan (5-HTP) is rate limiting in the formation of 5-HT. via tryptophan hydroxylase

56
Q

what does the drug P chlorophenylalanine do

A

The drug p-chlorophenylalanine (pCPA) is a selective inhibitor of tryptophan hydroxylase and causes a reduction in the tissue levels of 5-HT; it has no clinical use.

57
Q

What is the release of 5HT modulated by

A

the release of 5-HT is modulated by inhibitory somatodendritic 5-HT1A receptors and inhibitory 5HT1B/D autoreceptors.
- Over a short time period antagonists of these receptors will increase 5-HT release, whereas agonists will reduce 5-HT release.

58
Q

Receptor: 5-HT1A
Drug: Antagonist
Cell firing rate: Increase
- does it increase or decrease 5HT release

A

increases
- Activation of somatodendritic 5-HT1A receptors by an agonist such as 5-HT reduces cell firing and hence reduces 5-HT release: by blocking the actions of the agonist, an antagonist will increase the rate of cell firing and so increase 5-HT release.

59
Q

Receptor: 5-HT1A
Drug: Agonist
Cell firing rate: Decrease

5-HT release: ?increase or decrease

A

decrease
- An agonist of the inhibitory somatodendritic 5-HT1A receptors reduces cell firing; the number of action potentials invading the nerve terminals will decrease with a consequent reduction in 5-HT release

60
Q

Receptor: 5-HT1DB
Drug: Antagonist
Cell firing rate: No efffect

5-HT release: ? - increase or decrease

A

increase
Correct: 5-HT1D/B inhibitory autoreceptors are located on the terminals of the 5-HT neurone; when activated, they cannot affect the rate of cell firing but inhibit 5-HT release. An antagonist will block the inhibitory effect of 5-HT leading to an increase in 5-HT release.

61
Q

Receptor: 5-HT1DB
Drug: Agonist
Cell firing rate: No efffect

5-HT release: ? increase or decrease

A

decrease
Correct: 5-HT1D/B autoreceptors are inhibitory; when activated, they inhibit the release of 5-HT from nerve terminals but do not affect the rate of cell firing.

62
Q

what drugs are used to treat anxiety

A

Buspirone, ipsapirone and gepirone are relatively selective agonists of the somatodendritic autoreceptors. The drugs are used clinically to treat anxiety.

63
Q

what happens in long term treatment of buspirone

A

Long-term treatment with buspirone desensitizes 5-HT1A somatodendritic autoreceptors, resulting in increased release of 5-HT and potentiation of 5-HT transmission.

64
Q

what is desensitization

A

Desensitization indicates that a receptor has become less effective at transducing the agonist stimulus.
- One common cause is the prolonged exposure of receptors to agonist molecules; in the case of buspirone, activation of the inhibitory somatodendritic autoreceptors initially reduces release of 5-HT, but as desensitization develops 5-HT release actually increases above pre-drug levels.

65
Q

what drugs prevent the storage of 5HT

A

The active transport of 5-HT into the storage vesicles is driven by an ATPase.
- Drugs such as tetrabenazine compete with amines for their binding sites on amine transporters. thus preventing the storgae of 5HT into vesicles

66
Q

describe the characterstics of vesicular transporters

A

All are H+ pumping ATPases
The proton pump generates a H+ gradient
The uptake of one amine molecule is coupled to the efflux of 2H+

67
Q

what do reserpine and tetrabenazine do

A
  • these inhibiting the enzyme and blocks vesicular loading
  • therefore it depletes the nerve terminals of 5HT
  • reserpine will deplete levels of any amine whose vesicular storage is dependant on the same ATPase (such as dopamine, noradrenaline and adrenaline)
68
Q

what is buspirone a partial agonist for

A

Buspirone is a partial agonist of somatodendritic 5HT1A receptors and is used to treat anxiety.

69
Q

what do buspirone, ipsapirone and gepirone all do

A
  • They all alleviate the symptoms of anxiety but the response to treatment may not appear for 2 weeks.
  • This strongly suggests that their effects may involve a slow process of change in the receptors, which ultimately alters the dynamics of 5-HT transmission.
70
Q

what is sumatriptan an agonist of

A

Sumatriptan is a selective agonist of 5HT1B/D (also known as 5-HT1B) and 5-HT1D receptors

71
Q

what is sumatriptan used in treatment of

A

acute migraine attack, or cluster headache.

72
Q

What causes a migraine

A

During a migrainous headache, intracranial blood vessels become distended and oedematous due to activation of (trigeminal) nerve terminals and the subsequent release of neuropeptides

73
Q

How does sumatriptan work

A

Sumatriptan activates 5-HT receptors on the vascular smooth muscle (to induce vasoconstriction) and on the nerve endings (to reduce the release of neuropeptides

74
Q

what is ondanestron used in and what is it a selective antagonist for

A

Ondansetron is used in the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy and in post-operative nausea and vomiting. It is a selective 5-HT3 antagonist.

75
Q

what does ondansetron, granisetron and tropisteron do

A

Their anti-emetic actions are mediated both centrally (5-HT3 receptors in the area postrema) and peripherally (5-HT3 receptors on sensory nerves in parts of the gastro-intestinal tract).

76
Q

where do ketanserin and ritanserin act as antagonists

A

Ketanserin and ritanserin can act as antagonists at both 5-HT1A and 5-HT2 receptors.

77
Q

what is LSD

A

LSD itself is a non- selective agonist of 5-HT1 receptors

78
Q

What drugs selectively inhibit 5HT

A

Drugs which selectively inhibit the 5-HT transport include fluoxetine, paroxetine and sertraline, which are serotonin selective re-uptake inhibitors (SSRI).
Many tricyclic antidepressants also inhibit 5-HT reuptake, but are less selective than the SSRI.

79
Q

What are two monoamine oxidase inhibitors

A

irreversible MAOI and reversible MAOI;

- the latter are also known as RIMA.

80
Q

describe the 5HT transporter

A
  • The 5-HT transporter (also known as the re-uptake system) has been cloned and is known to belong to the family of Na+ and Cl⁻ dependent transporters.
  • The transporter is a single polypeptide chain that traverses the membrane 12 times.
81
Q

what are the other members of the family of the 5HT transporter

A
  • Other members of the family include transporters for dopamine, noradrenaline, GABA and glycine.
82
Q

What are the two forms of MAO

A

MAOA and MAOB .

83
Q

what does MAO do

A

Monoamine oxidase (MAO) oxidatively deaminates a range of amine substrates, including dopamine, noradrenaline and 5-HT.

84
Q

What are SSRI used to treat

A

depression.

85
Q

what is the mechanism of action of SSRI

A
  • Acutely they block 5-HT re-uptake and so potentiate 5-HT transmission.
  • Over time, the increased levels of 5-HT desensitize inhibitory 5HT1A somatodendritic autoreceptors, increasing 5-HT release.
86
Q

what do tricyclic antidepressants drugs do

A
  • Tricyclic drugs potentiate (increase) monoaminergic transmission.
  • Most tricyclics inhibit amine re-uptake (e.g. amitriptyline, 5-HT; imipramine , 5-HT and noradrenaline (NA); desipramine , NA) .
  • Some sensitize post-synaptic 5-HT receptors, others desensitize inhibitory alpha-2 adrenoceptors on 5-HT nerve terminals, and others potentiate NA transmission.
87
Q

What is an irreversible MAOI and what does it do

A
  • Irreversible MAOI (e.g. phenelzine and isocarboxazid) non- selectively inhibit both forms of MAO, and although effective antidepressants, they give rise to a number of side effects including the “cheese reaction”.
  • They probably work by desensitizing inhibitory alpha-2 receptors located on 5-HT and NA nerve terminals thereby increasing transmitter release and potentiating transmission.
88
Q

What is the cheese reaction

A

In the “cheese reaction”, patients treated with irreversible MAOI who ingest amines such as tyramine in their diet, suffer from a severe and potentially fatal rise in blood pressure. Tyramine is found in mature cheese – hence the term “cheese reaction”.

89
Q

What does RIMA do

A

RIMA (e.g. moclobemide) differ from the irreversible MAOI, in that they are reversible and are selective inhibitors of MAOA.
- Because of this, they have a shorter duration of action and the “cheese reaction” is much less severe (the risk of such a reaction is around 10 times less than with an irreversible IMAO).

90
Q

What causes a more severe cheese reaction

A

irreversible MAOI

91
Q

true or false

5-HT2c receptors may modulate the rate of production of cerebrospinal fluid

A

true

92
Q

true or false

5-HT4 receptors are positively coupled to adenylate cyclase

A

true

93
Q

true or false

5-HT5 receptors are coupled to inositol phospholipid turnover.

A

false - 5HT2 receptors are

94
Q

5-HT6 receptors mediate the effects of neuroleptic drugs.

true or false

A

false
- Although several neuroleptic drugs have high affinity for the 5-HT6 receptor, there is no evidence that their antipsychotic actions depend on this property.

95
Q

Overactivity of 5-HT is a cause of depression.

true or false

A

false

- Drugs successful in the treatment of depression potentiate 5-HT transmission.

96
Q

true or false

Drugs that potentiate transmission that is mediated by noradrenaline are ineffective in treating depression.

A

false
- Some drugs that selectively potentiate noradrenergic systems are effective antidepressants: however, their metabolites may also potentiate serotonergic systems.

97
Q

true or false

The symptoms of anxiety are alleviated by agonists of 5-HT1A receptors.

A

true

98
Q

true or false

anxiety Is commonly treated with drugs that reduce GABA-mediated inhibitory transmission

A

false
- Drugs the reduce GABA-mediated inhibitory transmission are anxiety provoking (anxiogenic).
Drugs most commonly used to treat anxiety are the benzodiazepines which potentiate the effects of GABA at the GABAA receptor complex.