CAL 3 Flashcards
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
- Synthesis
- Storage
- Release
- Activation of 5-HT receptors
- 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
- 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
what do the Gi/O protein coupled to the 5HT1A receptor do
The Gi/o protein coupled to 5-HT1A receptors also directly activates some K+ channels to reduce neuronal excitability.
26
Where is 5HT1A found ( subtype from the 5HT1 family) and what do they do
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
Where is 5HT1B found and what do they do ( subtype from the 5HT1 family)
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
Where is 5HT1D found and what do they do ( subtype from the 5HT1 family)
- 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
where are 5HT1E and 5HT1F found ( subtype from the 5HT1 family)
- 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
what are the 5HT2 subtypes coupled to and what do they do
- All three subtypes are coupled to inositol phosphate turnover to increase formation of diacylglycerol and inositol-1,4,5-triphosphate.
31
what is the classical subtype of 5-HT2 receptor
5-HT2A
32
The 5-HT2C receptor corresponds to the......
receptor previously known as 5-HT1C.
33
name the subtypes of the 5HT2 receptors
5-HT2A
5-HT2B
5-HT2C
34
where is 5HT2A found and what does it do (subtype of 5HT2 receptor)
- 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
Where is 5-HT2B found and what does it do (subtype of 5HT2 receptor)
- 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
where is 5-HT2C found and what does it do (subtype of 5HT2 receptor)
- 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
What receptor type is the 5HT3 receptor
Ligand gated, cation-selective ion channels which mediate membrane depolarization/neuronal excitation.
38
where is the 5HT3 receptor found
- 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
What does the 5HT3 receptor do
roles in emesis and possibly anxiety, neuronal migration and differentiation
- mediates fast excitatory transmission
40
What is the 5HT4 receptor coupled to
Positively coupled to adenylate cyclase by Gs.
41
Where is the 5HT4 receptor
High levels in limbic structures and the striatum, but role in the CNS unknown.
42
what does the 5HT4 receptor do
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
what are the two subtypes of 5HT5 receptors
5ht5A
| 5ht5B
44
what is the role of the 5HT5 receptors
Unknown transduction pathway, unknown roles.
45
where is 5ht5A and 5ht5B
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
What are 5HT6 AND 5HT7 coupled to
Both receptors are positively coupled to adenylate cyclase (coupling to the Gs protein).
47
where are 5HT6 and 5HT7 found
No peripheral expression of the 5-HT6 receptor detected; low levels of peripheral expression of the 5-HT7 receptor.
48
what drugs bind to 5HT6 and 5HT7
Several antidepressants bind with high affinity to the 5-HT6 receptor.
Several neuroleptics bind with high affinity to the 5-HT7 receptor.
49
why is increasing the intake of L-tryptophan in the diet only have a modest effect
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
why was L tryptophan withdrawn
The drug was withdrawn because of toxic effects (eosinophilia-myalgia syndrome
51
what was L tryptophan used to treat
L-tryptophan used to be given either alone or as add-on therapy in the treatment of depression
52
Why is L tryptophan an essential amino acid
L-tryptophan is an essential amino acid which, because of its indole side chain, is highly hydrophobic.
53
What can L tryptophan be oxidised to
L-tryptophan is a constituent of proteins and in addition to being the precursor of 5-HT, can also be oxidised to kynurenine.
54
wha does tryptophan hydroxylase require in order to work
Tryptophan hydroxylase requires molecular oxygen and reduced tetrahydrobiopterin.
55
What is the rate limiting step of the formation of 5HT
The formation of 5-hydroxytryptophan (5-HTP) is rate limiting in the formation of 5-HT. via tryptophan hydroxylase
56
what does the drug P chlorophenylalanine do
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
What is the release of 5HT modulated by
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
Receptor: 5-HT1A
Drug: Antagonist
Cell firing rate: Increase
- does it increase or decrease 5HT release
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
Receptor: 5-HT1A
Drug: Agonist
Cell firing rate: Decrease
5-HT release: ?increase or decrease
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
Receptor: 5-HT1DB
Drug: Antagonist
Cell firing rate: No efffect
5-HT release: ? - increase or decrease
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
Receptor: 5-HT1DB
Drug: Agonist
Cell firing rate: No efffect
5-HT release: ? increase or decrease
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
what drugs are used to treat anxiety
Buspirone, ipsapirone and gepirone are relatively selective agonists of the somatodendritic autoreceptors. The drugs are used clinically to treat anxiety.
63
what happens in long term treatment of buspirone
Long-term treatment with buspirone desensitizes 5-HT1A somatodendritic autoreceptors, resulting in increased release of 5-HT and potentiation of 5-HT transmission.
64
what is desensitization
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
what drugs prevent the storage of 5HT
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
describe the characterstics of vesicular transporters
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
what do reserpine and tetrabenazine do
- 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
what is buspirone a partial agonist for
Buspirone is a partial agonist of somatodendritic 5HT1A receptors and is used to treat anxiety.
69
what do buspirone, ipsapirone and gepirone all do
- 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
what is sumatriptan an agonist of
Sumatriptan is a selective agonist of 5HT1B/D (also known as 5-HT1B) and 5-HT1D receptors
71
what is sumatriptan used in treatment of
acute migraine attack, or cluster headache.
72
What causes a migraine
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
How does sumatriptan work
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
what is ondanestron used in and what is it a selective antagonist for
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
what does ondansetron, granisetron and tropisteron do
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
where do ketanserin and ritanserin act as antagonists
Ketanserin and ritanserin can act as antagonists at both 5-HT1A and 5-HT2 receptors.
77
what is LSD
LSD itself is a non- selective agonist of 5-HT1 receptors
78
What drugs selectively inhibit 5HT
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
What are two monoamine oxidase inhibitors
irreversible MAOI and reversible MAOI;
| - the latter are also known as RIMA.
80
describe the 5HT transporter
- 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
what are the other members of the family of the 5HT transporter
- Other members of the family include transporters for dopamine, noradrenaline, GABA and glycine.
82
What are the two forms of MAO
MAOA and MAOB .
83
what does MAO do
Monoamine oxidase (MAO) oxidatively deaminates a range of amine substrates, including dopamine, noradrenaline and 5-HT.
84
What are SSRI used to treat
depression.
85
what is the mechanism of action of SSRI
- 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
what do tricyclic antidepressants drugs do
- 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
What is an irreversible MAOI and what does it do
- 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
What is the cheese reaction
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
What does RIMA do
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
What causes a more severe cheese reaction
irreversible MAOI
91
true or false
| 5-HT2c receptors may modulate the rate of production of cerebrospinal fluid
true
92
true or false
| 5-HT4 receptors are positively coupled to adenylate cyclase
true
93
true or false
| 5-HT5 receptors are coupled to inositol phospholipid turnover.
false - 5HT2 receptors are
94
5-HT6 receptors mediate the effects of neuroleptic drugs.
| true or false
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
Overactivity of 5-HT is a cause of depression.
| true or false
false
| - Drugs successful in the treatment of depression potentiate 5-HT transmission.
96
true or false
| Drugs that potentiate transmission that is mediated by noradrenaline are ineffective in treating depression.
false
- Some drugs that selectively potentiate noradrenergic systems are effective antidepressants: however, their metabolites may also potentiate serotonergic systems.
97
true or false
| The symptoms of anxiety are alleviated by agonists of 5-HT1A receptors.
true
98
true or false
| anxiety Is commonly treated with drugs that reduce GABA-mediated inhibitory transmission
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.
