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Neurobiology of Disease 4 Flashcards

1
Q

Define ‘depression’. (1)

A

Persistent feelings of sadness, hopelessness, or loss of interest in life which can last for weeks or months.

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2
Q

DSM-V criteria is used to diagnose depression. Patients must have experienced at least 5 out of 9 symptoms in the same 2 weeks.

Name the two symptoms (one of which must feature). (2)

Then name the other seven symptoms. (7)

A
  • Depressed mood
  • Loss of interest or pleasure
  • Change in weight/appetite
  • Insomnia or hypersomnia
  • Psychomotor retardation or agitation
  • Loss of energy or fatigue
  • Feelings of worthlessness or guilt
  • Impaired concentration or indecisiveness
  • Suicidal ideation or suicide attempt
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3
Q

Which mental health condition is being described? (1)

‘A mental health condition that affects moods, which can swing from one extreme to another.’

A

Bipolar disorder

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4
Q

Name the two extreme moods which are experienced in bipolar disorder. (2)

How long do these ‘moods’ typically last? (1)

A
  • Depression
  • Mania

Each mood can last for several weeks at a time

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5
Q

Bipolar disorder used to be known by what other name? (1)

A

Manic depression

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6
Q

Give a definition of mania, including how long it must have lasted for and how often symptoms are present. (3)

A

Abnormally and persistently elevated/irritable mood

lasting at least a week

and present most of the day nearly every day.

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7
Q

According do the DSM-V at least 3 symptoms have to be present to be diagnosed with mania.

What are the seven possible symptoms? (7)

A
  • Inflated self-esteem and grandiosity
  • Decreased need for sleep
  • More talkative than usual or pressure to keep talking
  • Flight of ideas or subjective experience that thoughts are racing
  • Distractibility
  • Increase in goal-directed activity
  • Excessive involvement in activities with high potential for painful consequences
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8
Q

Briefly describe the monoamine hypothesis of depression and mania. (2)

A

Depression is due to a functional deficit of monoamine neurotransmitters

mania is due to a functional excess.

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9
Q

Name three monoamine neurotransmitters. (3)

A

Noradrenaline

Dopamine

Serotonin

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10
Q

Give two pieces of pharmacological evidence that support the monoamine hypothesis of depression. (2)

A
  • Drugs that increase monoamine neurotransmission improve mood
  • Drugs that reduce monoamine neurotransmission lower mood
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11
Q

One piece of evidence that supports the monoamine hypothesis of depression is that drugs that increase monoamine neurotransmission improve mood.

Give two examples of this. (2)

A

Tricyclic antidepressants block monoamine reuptake and improve mood.

Monoamine oxidase inhibitors inhibit monoamine metabolism and improve mood.

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12
Q

One piece of evidence that supports the monoamine hypothesis of depression is that drugs that reduce monoamine neurotransmission lower mood.

Give an example of this. (1)

A

Reserpine, a-methyltyrosine, and methyldopa all inhibit monoamine synthesis or storage

and all lower mood.

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13
Q

Briefly describe four shortcomings in the monoamine hypothesis of depression. (4)

A
  • Doesn’t clarify the pathophysiology of depression
  • Drugs like cocaine and amphetamine enhance monoamine neurotransmission but aren’t antidepressant
  • Some clinically effective antidepressants don’t affect monoamines
  • Doesn’t explain the delayed therapeutic onset or treatment resistance (30% of people don’t respond)
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14
Q

Briefly describe the issue of delayed therapeutic onset with antidepressants. (3)

ie, what don’t we understand as scientists, why is it confusing?

A

SSRIs elevate synaptic 5HT within hours

Side effects also appear within hours

However antidepressant effects take about 3 weeks to occur

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15
Q

Name a neuroendocrine pathway which may be implicated in depression. (1)

A

HPA axis

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16
Q

Complete the passage relating to the HPA axis in depression. (6)

Depressed patients display HPA axis …………………

There is increased …………………. in saliva, plasma, and urine.
Increased ……………………… in CSF and limbic brain regions.
Increased size and activity of …………………………….. and ………………………..
And impaired …………………………….. mechanisms.

A

Hyperactivation

Cortisol

Corticotropin releasing hormone

Pituitary gland

Adrenal glands

Negative feedback

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17
Q

How might antidepressant drugs affect the HPA axis to treat depression? (1)

A

Enhance negative feedback to reduce HPA axis hyperactivity.

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18
Q

How is the volume of the hippocampus affected in depression? (1)

A

Reduced by about 10%

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19
Q

The volume of the hippocampus is reduced in depression.

Briefly name and describe two mechanisms by which this may occur. (4)

A

NEUROPLASTICITY HYPOTHESIS:

  • Atrophy of mature neurones (shortened dendrites and/or decreased spinal density)

NEUROGENESIS HYPOTHESIS:

  • Decreased adult neurogenesis (fewer new neurones and neural precursors)
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20
Q

Describe a piece of evidence supporting the neuroplasticity hypothesis of depression. (1)

A

Ketamine (a rapid onset antidepressant) increases number and function of dendritic spines in the PFC

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21
Q

Describe a piece of evidence supporting the neurogenesis hypothesis of depression. (1)

A

Many antidepressants are known to increase adult neurogenesis.

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22
Q

Name a molecule which may be involved in pathology and treatment responses, according to the neuroplasticity and neurogenesis hypothesis of depression. (1)

A

BDNF

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23
Q

Briefly describe four pieces of evidence supporting the theory that inflammation may be involved in depression. (4)

A
  • Patients with depression have increased inflammatory markers (cytokines, chemokines, acute-phase proteins)
  • Preclinical studies show that inflammatory markers induce depressive symptoms
  • Inflammation can precipitate depression in hepatitis or cancer patients treated with INFa or IL-2
  • Systemic diseases with an inflammatory component increase risk of depression (eg. RA or IBD)
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24
Q

Suggest a non-pharmacological treatment for depression. (1)

What is the aim of this treatment? (1)

A

Cognitive behavioural therapy (CBT)

Aims to stop negative cycle that influences behaviour and emotion.

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25
Q

Briefly describe the negative cycle of thoughts and behaviours associated with depression. (4)

A
  • Low mood
  • Altered physical functioning (eg. sleep, appetite)
  • Altered behaviours (eg. withdrawal, work absence)
  • Negative thoughts about self
  • Back to low mood
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26
Q

Give three general mechanisms that pharmacological management of depression aims to work via. (3)

A
  • Inhibit reuptake of monoamine neurotransmitters
  • Block presynaptic receptors that inhibit monoamine release
  • Inhibit monoamine oxidase
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27
Q

Give a reason which monoamine inhibitors aren’t really used to treat depression anymore. (1)

Give two examples of MAOIs which have been used in the past. (2)

A

Can have serious side effects (including food interactions)

Phenelzine

Tranylcypromine

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28
Q

Give five possible classes of drugs which may be effective in depression (not MAOIs). (5)

A

SSRI

Tricyclic antidepressants

SNRI

Noradrenaline reuptake inhibitor

Mirtazapine

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29
Q

Describe two theories behind why antidepressants, such as SSRIs, have a delayed therapeutic effect. (7)

A
  • Inhibition of SERT leads to increased 5HT
  • More 5HT binds presynaptic autoreceptors
  • Inhibition of 5HT release
  • Over time, presynaptic receptors desensitise
  • Therapeutic effects can then be felt
  • Also, antidepressants work by altering gene expression and synaptic plasticity
  • And these effects take time to kick in
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30
Q

How do SSRIs alter monoamine neurotransmission? (2)

A

Increase synaptic serotonin

By inhibiting SERT transporter and reuptake

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31
Q

Give four examples of SSRIs that can be used to treat depression. (4)

A
  • Citalopram
  • Fluoxetine
  • Paroxetine
  • Sertraline
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32
Q

Give two reasons why SSRIs are the first line treatment for depression. (2)

A
  • Favourable side-effect profile
  • Less toxic in overdose
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33
Q

Give two examples of tricyclic antidepressants (TCA) which can be used to treat depression. (2)

A

Amitriptyline

Imipramine

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34
Q

Describe how tricyclic antidepressants alter monoamine neurotransmission. (2)

A
  • Increase synaptic 5HT and NA
  • By inhibiting reuptake
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35
Q

Give three side effects that are seen with tricyclic antidepressants. (3)

A
  • Sedative
  • Anticholinergic (dry mouth, blurred vision)
  • Cardiovascular (can be fatal in overdose)
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36
Q

Why can tricyclic antidepressants have sedative effects? (1)

A

Because they can act as H1 antagonists

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37
Q

Give two examples of SNRIs which can be used to treat depression. (2)

A

Venlafaxine

Duloxetine

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38
Q

Describe how SNRIs alter monoamine neurotransmission. (2)

A

Increase synaptic 5HT and NA

by inhibiting reuptake

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39
Q

Given that SNRIs may be more effective than SSRIs in treating depression, why aren’t SNRIs used as the first line treatment? (1)

A

They can increase blood pressure

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40
Q

Name a noradrenaline reuptake inhibitor which can be used to treat depression. (1)

A

Reboxetine

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41
Q

How is mirtazapine thought to enhance NA and 5HT neurotransmission? (1)

A

By blocking presynaptic a2 and 5HT2 autoreceptors (which would normally inhibit NA and 5HT release)

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42
Q

Give a side effect often seen when using mirtazapine to treat depression. (1)

A

Sedative

(However this may be helpful if the patient is experiencing sleeping difficulties)

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43
Q

Give three possible next generation treatments for depression. (3)

A
  • Ketamine
  • Vagal nerve stimulation
  • Psychedelics
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44
Q

What receptors are targeted by ketamine, as used to treat depression? (1)

A

Glutamate NMDA receptor antagonist

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45
Q

Give an advantage and a disadvantage of using ketamine to treat depression. (2)

A

ADVANTAGE:

  • Rapid-onset activity which may last for several weeks

DISADVANTAGE:

  • Cannot be given in an outpatient setting (given as low-dose infusion)
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46
Q

Give two potential mechanisms that ketamine may use to help treat depression. (2)

*Not NMDA antagonist

A
  • mTOR signalling (mechanistic targeting of rapamycin)
  • BDNF
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47
Q

When might vagal nerve stimulation be useful in treating depression? (1)

A

For treatment-resistant depression which has not responded to drugs.

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48
Q

Psychedelics used to treat depression often target what receptor (and how)? (2)

A

5HT2A receptor

Agonists

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49
Q

Give an example of a psychedelic why may be effective in treating depression. (1)

A

Psilocybin COMP360

(Currently in phase III clinical trials)

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50
Q

Describe one confounding factor to take into account when using and evaluating the use of psychedelic drugs to treat depression. (2)

A

Patients must receive psychotherapeutic input while receiving the drug.

Are the positive effects due to drug or psychotherapeutic input?

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51
Q

Suggest three possible pharmacological therapies to treat mania in bipolar disorder. (3)

A
  • Lithium
  • Antipsychotics
  • Anticonvulsants
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52
Q

What is the exact cellular mechanism by which lithium alters neurotransmission in the treatment of bipolar disorder? (1)

A

Unknown

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53
Q

Give three effects of lithium on neurotransmission in the treatment of bipolar disorder. (3)

A
  • Reduces excitatory DA neurotransmission
  • Reduces excitatory glutamate neurotransmission
  • Increases inhibitory GABA neurotransmission
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54
Q

Give a major drawback with using lithium to treat bipolar disorder. (1)

A

Has a very narrow therapeutic window so careful monitoring is essential.

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55
Q

What is the therapeutic window (blood concentration) for lithium when treating bipolar disorder? (1)

A

0.5-1.0mmol/L

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56
Q

Give ten possible effects that can be seen with blood concentrations of lithium over 1.0mmol/L. (10)

A
  • Severe diarrhoea
  • Vomiting or anorexia
  • Muscle twitching
  • Dehydration
  • Drowsiness
  • Confusion
  • Muscle weakness
  • Slurred speech
  • Vertigo
  • Blurred vision
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57
Q

Give six possible effects that can be seen with blood concentrations of lithium over 2.0mmol/L. (6)

A
  • Convulsions
  • Renal failure
  • Electrolyte imbalance
  • Hypotension
  • Clouding of consciousness
  • Coma and death
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58
Q

Name four antipsychotics that could be used to treat bipolar disorder. (4)

A
  • Olanzapine
  • Quetiapine
  • Risperidone
  • Cariprazine
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59
Q

How do antipsychotics affect monoamine transmission? (2)

A

Reduce monoamine activity

by antagonising D2 and 5HT2A receptors

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60
Q

Give a particularly troubling side effect of antipsychotic drugs, as used to treat bipolar disorder. (1)

A

Weight gain

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61
Q

Give three examples of anticonvulsants which could be used to treat bipolar disorder. (3)

A
  • Valproate
  • Carbamazepine
  • Lamotrigine
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62
Q

Describe a caution that must be taken into account when using valproate to treat bipolar disorder. (2)

A

It increases risk of birth defects and developmental disorders

so must be avoided in pregnancy.

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63
Q

When serotonin was first discovered in blood serum (by Maurice Rapport and Irvine Page), what was its effects shown to be on tissue? (1)

A

Increase tension and contract arteries

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64
Q

Name the molecular structure of serotonin. (1)

A

5-hydroxytryptamine (5-HT)

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65
Q

Give the two components of the molecular structure of serotonin. (2)

A

Indole ring

Amine group

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66
Q

Monoamine neurotransmitters can be further classified into groups based on their molecular structures. For example, dopamine and noradrenaline are both monoamines and catecholamines.

What further category is serotonin classified into? (1)

A

Indolamines

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67
Q

Serotonin can be classified as an indolamine neurotransmitter.

Give another example of an indolamine. (1)

A

Melatonin

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68
Q

Suggest a category of drugs of abuse which have a similar structure to indolamine neurotransmitters. (1)

A

Hallucinogenic or psychedelic drugs

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69
Q

There are two groups of serotonergic neurones in the brain.

Name the two general locations where their cell bodies are located. (2)

A

Rostral (and median) raphe nuclei

Caudal raphe nuclei

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70
Q

The rostral (and median) raphe nuclei contain serotonergic neurones.

Give four areas of the CNS where these neurones project to. (4)

A
  • Forebrain
  • Thalamus
  • Hippocampus
  • Cerebellum
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71
Q

The caudal raphe nuclei contain serotonergic neurones.

Give two areas of the CNS where these neurones project to. (2)

A

Spinal cord

Cerebellum

72
Q

The rostral (and median) raphe nuclei contain serotonergic neurones.

Name three rostral and median raphe nuclei. (3)

A

Nucleus raphe pontis

Median raphe nucleus

Nucleus raphe dorsalis

73
Q

The caudal raphe nuclei contain serotonergic neurones.

Name three caudal raphe nuclei. (3)

A
  • Nucleus raphe obscurus
  • Nucleus raphe pallidus
  • Nucleus raphe mangus
74
Q

What percentage of total body serotonin is produced in the CNS? (1)

Where else is serotonin produced/contained in the body? (2)

A

2%

  • 90% produced by enterochromaffin cells in GI tract
  • 8% located in platelets
75
Q

Serotonin is synthesised in a two step process.

Briefly describe the first step (what is converted to what, and what is the molecular change)? (2)

A

Tryptophan converted to 5-hydroxytryptophan

By addition of a hydroxyl group

76
Q

Name the enzyme which converts tryptophan to 5-hydroxytryptophan in the synthesis of serotonin. (1)

A

Tryptophan hydroxylase

77
Q

Name the amino acid precursor from which serotonin is synthesised. (1)

A

Tryptophan

78
Q

Serotonin is synthesised in a two step process.

Briefly describe the second step (what is converted to what, and what is the molecular change)? (2)

A

5-hydroxytryptophan converted to serotonin

By removal of a carboxyl group

79
Q

Name the enzyme which converts 5-hydroxytryptophan to serotonin. (1)

A

L-aromatic amino acid decarboxylase

80
Q

What is the rate limiting step in the synthesis of serotonin? (1)

A

Tryptophan hydroxylase conversion

81
Q

Is tryptophan hydroxylase a substrate specific enzyme or a non-substrate specific enzyme? (1)

A

Substrate specific

82
Q

Name three molecules (or other activators) which are required for the enzyme tryptophan hydroxylase to be functional. (3)

A
  • Tetrahydrobiopterin (BH4)
  • NADPH
  • Metal ion (such as iron or copper)
83
Q

Give two roles of the L-aromatic amino acid decarboxylase enzyme. (2)

A

Synthesis of dopamine

Synthesis of serotonin

84
Q

Complete the sentence relating to serotonin synthesis. (2)

Brain serotonin synthesis is dependent on the amount of …………………….. crossing the …………………

A

Tryptophan

BBB

85
Q

Give three things that alter the amount of tryptophan crossing the BBB, and therefore alter the rate of serotonin synthesis. (3)

A
  • Amount bound to albumin (only free plasma tryptophan can cross BBB)
  • Other neutral AAs compete with free tryptophan for entry across BBB
  • Plasma cortisol, which decreases plasma free tryptophan concentrations
86
Q

Briefly describe how increased plasma cortisol may lead to depression. (3)

A
  • Increased cortisol decreases plasma free tryptophan
  • So less can cross the BBB
  • And less tryptophan available for serotonin synthesis
87
Q

Name two enzymes (in the order which they work) which metabolise serotonin. (2)

A

monoamine oxidase

aldehyde dehydrogenase

88
Q

True or false? Explain your answer if necessary. (1)

Serotonin is metabolised in both neurones and glial cells.

89
Q

The first step of serotonin metabolism is degradation by MAO.

Name the intermediate produced. (1)

A

5-hydroxyindoleacetaldehyde

90
Q

The second step of serotonin metabolism is degradation by aldehyde dehydrogenase.

Name the intermediate produced. (1)

A

5-hydroxyindoleacetic acid (5-HIAA)

91
Q

5-HIAA is produced when serotonin is metabolised.

How does the body get rid of 5-HIAA? (1)

A

Excreted by the kidneys

92
Q

What can measurement of the 5-HIAA/5-HT ratio indicate? (2)

A
  • 5HT turnover
  • Neuronal activity
93
Q

How much homology is there between the enzymes monoamine oxidase A and B? (1)

94
Q

True or false? Explain your answer if appropriate. (1)

Both monoamine oxidase A and monoamine oxidase B enzymes are found in both neurones and glial cells.

95
Q

The enzyme monoamine oxidase A is found in neurones and glial cells.

Give another location in the body where it is found. (1)

96
Q

The enzyme monoamine oxidase B is found in neurones and glial cells.

Give another location in the body where it is found. (1)

97
Q

Where exactly in the cell are MAO A and B enzymes found? (1)

A

Bound to the outer mitochondrial membrane

98
Q

Monoamine oxidase A is mainly used to metabolise what neurotransmitter/s?

A
  • Serotonin
  • Noradrenaline
  • Adrenaline
99
Q

Monoamine oxidase B is mainly used to metabolise what neurotransmitter/s?

100
Q

Give two medical conditions, which, in the past, have shown improvement due to blockade of monoamine oxidase enzymes. (2)

A

Depression

Panic disorder

101
Q

Give two examples of pharmaceuticals or other molecules which are able to inhibit monoamine oxidase A. (2)

A

Clorgyline

Pargyline

102
Q

Give the name of the serotonin reuptake transporter. (1)

A

Serotonin transporter protein (SERT)

103
Q

On which neurone (presynaptic or postsynaptic) is the SERT protein located? (1)

A

Presynaptic

104
Q

What is the main form of serotonin deactivation in the synaptic cleft? (1)

A

Reuptake by SERT

105
Q

How many membrane-spanning segments does the SERT protein have? (1)

106
Q

The SERT protein can be modified by glycosylation or phosphorylation.

Does glycosylation occur on the extracellular segments or intracellular segments? (1)

A

Extracellular

107
Q

The SERT protein can be modified by glycosylation or phosphorylation.

Does phosphorylation occur on the extracellular segments or intracellular segments? (1)

A

Intracellular

108
Q

Briefly describe the molecular mechanism by which SERT takes serotonin up into the presynaptic neurone. (4)

Is the SERT protein classed as an antiporter or symporter? (1)

A
  • SERT binds 2xNa, 5HT, and Cl
  • Transporter flips inside cell due to membrane potential
  • Bound 5HT and 1xNa released into cytoplasm
  • SERT then binds a K to flip back outside the cell membrane (K released before next uptake)

Symporter

109
Q

Name the gene which codes for the SERT transporter. (1)

What chromosome is this gene found on? (1)

A

SLC6A4 gene

Found on chromosome 17

110
Q

Describe the polymorphisms found in the promotor region of the SLC6A4 gene, which codes for the SERT transporter. (2)

Describe the protein expression and phenotype associated with (one of) these alleles. (2)

A
  • Short allele (14 repeats)
  • Long allele (16 repeats)

Short allele leads to less gene transcription.

Associated with anxiety-related personality traits.

111
Q

How many distinct serotonin receptors are there? (1)

How many families can these receptors be classified into? (1)

A

14 distinct receptors

Belonging to 7 different families

112
Q

True or false? Explain your answer if appropriate. (1)

All serotonin receptors are encoded by different genes.

113
Q

Name the families of serotonin receptors. (7)

A

5HT1

5HT2

…

5HT7

114
Q

All serotonin receptors have how many membrane-spanning segments? (1)

115
Q

All serotonin receptors have 7 membrane-spanning segments.

How many intracellular loops does each receptor have? (1)

How many extracellular loops does each receptor have? (1)

A

3 intracellular

3 extracellular

116
Q

Tue or false? Explain your answer if appropriate. (1)

All serotonin receptors display huge variation, with only 10% amino acid homology between them.

A

False - they have 40-50% AA homology

117
Q

Which one/s of the following sentences best describes serotonin receptors? (1)

a) all serotonin receptors are excitatory

b) all serotonin receptors are GPCRs

c) all serotonin receptors are inotropic

d) all serotonin receptors are inhibitory

e) none of the above

A

e) none of the above

  • Mix of excitatory and inhibitory
  • All are GPCRs except from 5HT3 receptors
118
Q

Which family of serotonin receptors are ion channels? (1)

119
Q

Which families of serotonin receptors are GPCRs coupled to Gi? (2)

120
Q

Which families of serotonin receptors are GPCRs coupled to Gs? (3)

A

5HT4

5HT6

5HT7

121
Q

Which family of serotonin receptors are GPCRs coupled to Gq? (1)

122
Q

Name the specific serotonin receptors in the 5HT3 family. (3)

A

5HT3a

5HT3b

5HT3c

123
Q

Name the specific serotonin receptors in the 5HT1 family. (3)

A

5HT1a

5HT1b

5HT1d

124
Q

Name the specific serotonin receptors in the 5HT5 family. (2)

A

5HT5a

5HT5b

125
Q

Name the specific serotonin receptors in the 5HT2 family. (3)

A

5HT2a

5HT2b

5HT2c

126
Q

Which families of serotonin receptors only contain one subtype? (3)

A

5HT4

5HT6

5HT7

127
Q

5HT3 receptors are ligand-gated ion channels.

What ions are these channels permeable to? (2)

128
Q

5HT channel odd ones out (4):

All receptors are located postsynaptically except for ……………….

All receptors are excitatory expect for …………………. and ………………………

All receptors are GPCRs except for …………………

***All answers are families of receptors, not individual receptors.

A

5HT1

5HT1

5HT5

5HT3

129
Q

Which family of serotonin receptors act as autoreceptors on the presynaptic neurone? (1)

130
Q

The 5HT1 family of serotonin receptors act as autoreceptors on the presynaptic neurone.

Where specifically on the cell are 5HT1a receptors located? (1)

A

Dendrites, cell bodies, and axons.The 5HT1 family of serotonin receptors act as autoreceptors on the presynaptic neurone.

131
Q

The 5HT1 family of serotonin receptors act as autoreceptors on the presynaptic neurone.

What physiological effect do 5HT1a receptors have on the neurone to result in decreased serotonin release? (1)

A

Decreases neuronal firing rate

132
Q

The 5HT1 family of serotonin receptors act as autoreceptors on the presynaptic neurone.

Where specifically on the cell are 5HT1b receptors located? (1)

A

Axon terminal

133
Q

The 5HT1 family of serotonin receptors act as autoreceptors on the presynaptic neurone.

What physiological effect do 5HT1b receptors have on the neurone to result in decreased serotonin release? (1)

A

Signalling pathways within the presynaptic terminal (no effect on firing rate)

134
Q

True or false? Explain you answer if appropriate. (1)

As well as being coupled to G protiens, 5HT receptors may have other effects and functions within a cell.

A

True - can be in a range of different cell types

135
Q

Give a role of 5HT in microglia and astrocytes. (1)

A

Cytokine signalling

136
Q

Give a role of 5HT in oligodendrocytes. (1)

A

Myelination

137
Q

What general higher function of the brain is serotonin involved in? (1)

138
Q

Give eight general physiological roles of 5HT. (8)

A
  • Sleep
  • Body temperature
  • Food intake
  • Cognition
  • Mood
  • Vomiting
  • Pain perception
  • Neuroendocrine function (eg. cortisol)
139
Q

Very briefly describe how serotonin may act to regulate neuroendocrine function. (1)

A

By acting on hypothalamic neurones with 5HT receptors

(Particularly 5HT2)

140
Q

Very briefly describe how serotonin may act to affect sleep. (1)

A

Serotonin is a precursor for melatonin, which regulates biological clocks and circadian rhythm.

141
Q

Name four medical conditions which are thought to be affected by alterations in serotonergic neurotransmission. (4)

A
  • Migraine
  • Epilepsy
  • Depression
  • Anxiety
142
Q

Very briefly describe the change to 5HT neurotransmission seen in migraine. (1)

A

Chronically low 5HT

143
Q

Very briefly describe the change to 5HT neurotransmission seen in epilepsy. (1)

A

Alterations in 5HT receptor binding (1a, 2c, 3, 7)

144
Q

Very briefly describe the change to 5HT neurotransmission seen in depression. (1)

A

Reduced CNS 5HT

145
Q

Very briefly describe the change to 5HT neurotransmission seen in anxiety. (1)

A

SERT mutations alter 5HT neurotransmission

146
Q

Complete the sentence relating to serotonin and memory. (2)

Many studies have experimented with ………………….. receptors and their effects on memory.

They seem to ……………………. (agree/disagree) on the conclusion.

A

5HT4

disagree

147
Q

Many studies regarding the effects of serotonin on memory seem to disagree in their conclusions.

Give 3 reasons why different studies may have come up with different conclusions. (3)

A
  • Performed under different conditions
  • Different 5HT4 agonists
  • Different stimuli (trains of actions potentials) in different areas of the hippocampus
148
Q

Is serotonin thought to have an effect on LTP or LTD? (1)

A

Both have been hypothesised

149
Q

Describe two experimental methods which can be used to assess the effects of 5HT on memory. (2)

A
  • Brain imaging to look at neuronal plasticity
  • Optogenetics to see results of stimulating neurones
150
Q

Briefly describe how you would use optogenetics to investigate the effects of serotonin on memory. (4)

A
  • Light activation to increase neuronal activity
  • On serotonergic neurone terminals in CA1 of hippocampus
  • While rodent is subjected to memory task (eg. Morris water maze)
  • Record and assess outcome compared to control group
151
Q

In an experiment using optogenetics to activate serotonergic nerve terminals and assess how this affects memory, ChR2 mice spent more time in the target zone of the Morris water maze.

What does this suggest about the effects of serotonin on memory formation in this particular experiment? (1)

A

Serotonin improved memory

152
Q

Hallucinogenic drugs tend to have similar structures to which neurotransmitter? (1)

153
Q

What is the name of the hallucinogenic compound found in magic mushrooms? (1)

A

Psilocybin

154
Q

Give three symptoms/effects experienced with psilocybin. (3)

A
  • Euphoria
  • Hallucinations
  • Altered perceptions
155
Q

Psilocybin is a drug of abuse.

What receptors does it act on in the nervous system? (1)

A

Serotonergic

156
Q

Describe what is seen in PET 5HT ligand binding studies when psilocybin is added. (2)

A

Signal is reduced

because psilocybin competes with ligand to bind to serotonin receptors.

157
Q

Give three hallucinogenic drugs which all have a similar structure to serotonin. (3)

A
  • Psilocybin
  • LSD
  • DMT
158
Q

Give three symptoms/effects of LSD. (3)

A
  • Intensified thoughts and emotions
  • Altered sensory perception
  • Visual and auditory hallucinations (at high doses)
159
Q

Complete the passage relating to a hallucinogenic drug. (5)

DMT stands for ………………………., which is a hallucinogenic drug.
It is a derivative and structural analogue of ……………………..

A

Dimethyltryptamine

tryptamine/5-hydroxytryptamine

160
Q

What is the usual source of DMT? (1)

Eg. synthetic, plant, derived from natural drug

161
Q

Which specific serotonin receptors do hallucinogenic drugs act on? (2)

What intracellular signalling pathway is activated, and describe this. (3)

A

5HT2a

5HT2c

Coupled to Gq

Produce IP3 and DAG

Activate calcium and PKC pathway

162
Q

Name the mechanism by which some, but not all 5HT receptor agonists are hallucinogenic. (1)

A

Biased agonism

163
Q

Briefly describe how biased agonism results in some 5HT receptor agonists being hallucinogenic and some not. (3)

A
  • Some agonists are able to stabilise certain receptor conformations
  • These conformations selectively activate some signalling pathways but not others
  • Which may cause hallucinations
164
Q

In which brain location is melatonin synthesised from serotonin? (1)

A

Within the pineal gland

165
Q

Give three functions of melatonin. (3)

A
  • Controls sleep patterns
  • Controls hormone rhythms
  • Strong antioxidant
166
Q

How can melatonin play a role in preventing ageing, delaying senescence, and enhancing lifespan (in Drosophila)? (1)

A

Because it is an antioxidant

167
Q

Melatonin is synthesised from serotonin in a two step process.

Describe the first step. (2)

  • What is converted to what?
  • By what enzyme?
A

Serotonin converted to N-acetyl serotonin

By serotonin N-acetyltransferase

168
Q

Melatonin is synthesised from serotonin in a two step process.

Describe the second step. (2)

  • What is converted to what?
  • By what enzyme?
A

N-acetyl serotonin converted to melatonin

By 5-hydroxyindole-O-methyltransferase

169
Q

Briefly describe how production of melatonin is controlled in a circadian manner. (3)

A

N-acetyltransferase enzyme expressed in a circadian manner

Expressed less during the day

Because it degrades in the light

170
Q

Give two melatonin receptors found in mammals. (2)

Also give another receptor found in amphibians and birds. (1)

A

MT1 and MT2 found in mammals

MT3 found in amphibians and birds

171
Q

True or false? Explain your answer if appropriate. (1)

MT receptors are only expressed in the CNS.

A

False - they are expressed throughout the entire body

172
Q

Give two regions of the CNS where melatonin receptors are prominently expressed. (2)

A
  • Hippocampus
  • Hypothalamus
173
Q

Describe how melatonin binding to the MT1 receptor is able to regulate the circadian rhythm. (3)

A
  • CREB pathway activated
  • Changes in DNA transcription
  • Specifically the transcription of the clock protein, PER
174
Q

Inappropriate light exposure and disruption of melatonin synthesis may have several consequences.

Give a disease which may be caused by this. (1)

A

Alzheimer’s disease

175
Q

Describe, very simply, how disruption of melatonin synthesis may contribute to Alzheimer’s disease. (3)

A
  • Circadian dysfunction plays a role in amyloid plaque and tau changes
  • Less melatonin leads to oxidative stress
  • Neuronal degeneration and Alzheimer’s
176
Q

A transgenic mouse model of AD was produced (Tg2576).

Treatment with melatonin had what effect on amyloid-beta load? (1)

What other effect was seen? (1)

A

Melatonin reduced beta amyloid load

Survival was enhanced

177
Q

Describe a mechanism which explains how a lack of melatonin may be able to contribute to amyloid plaque formation in Alzheimer’s. (4)

A
  • Melatonin normally inhibits BACE1 and presenilin 1
  • These genes encode beta-secretase and gamma-secretase
  • So lack of melatonin increases these enzymes
  • And promotes processing of APP via the amyloidogenic pathway

Neuroscience Y2S2 (15 decks)

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