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Cellular Neuroscience > Catecholaminergic Transmission > Flashcards

Catecholaminergic Transmission Flashcards

1
Q

Catecholamines include which three NTs?

A

Adrenaline.
Noradrenaline.
Dopamine.

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2
Q

What are the two structural components that all catecholamines consist of?

A

Catechol nucleus.
Amine group.

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3
Q

The synthesis of all catecholamines begins with the synthesis of what?

A

Dopamine.

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4
Q

How is L-dopa synthesised?

A

Tyrosine hydroxylase adds a hydroxyl group to tyrosine.

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5
Q

How is dopamine synthesised from L-dopa?

A

Dopa decarboxylase removes a carboxyl group from L-dopa.

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6
Q

How does tyrosine reach the brain to be converted into L-dopa and then dopamine?

A

Active transport.

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7
Q

What is the rate-limiting enzyme for dopamine synthesis?

A

Tyrosine hydroxylase (TH).

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8
Q

Why must TH be actively transported into the brain?

A

It must penetrate the BBB.

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9
Q

What can increase TH activity?

A

Catecholamine release through transcriptional, translational and posttranslational regulation.

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10
Q

How does chronic environmental stress affect TH expression?

A

Upregulates it.

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11
Q

Name three drugs that upregulate TH expression.

A

Caffeine.
Nicotine.
Morphine.

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12
Q

What class of drugs downregulate TH expression?

A

Antidepressants.

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13
Q

Peripheral administration of L-dopa can be used to increase dopamine synthesis to treat PD. Why?

A

This bypasses the TH rate-limiting step and penetrates the BBB.

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14
Q

Which transporter is used in reuptake of dopamine into the axon terminal?

A

DAT (dopamine transporter).

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15
Q

Which two enzymes break down dopamine after reuptake into axon terminal?

A

MAO (monoamine oxidase).
COMT (catechol-O-methyltransferase).

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16
Q

Name the two MAO isoforms.

A

MAOa.
MAOb.

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17
Q

Which NTs can MAO metabolise?

A

All catecholamines.
5-HT.

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18
Q

In which neurons is MAOa expressed?

A

Dopaminergic and noradrenergic neurons.

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19
Q

In which neurons is MAOb expressed?

A

5-HT neurons (axons contain MAOa).

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20
Q

Which MAO isoform has a higher affinity for dopamine?

A

MAOa = MAOb.
They have the same affinity.

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21
Q

Which MAO isoform has a higher affinity for noradrenaline and 5-HT?

A

MAOa.

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22
Q

MAO inhibitors (MAOIs) can be used to treat what?

A

Parkinson’s disease (PD).

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23
Q

Explain why MAOIs are used to treat PD.

A

MPTP is a dopamine neurotoxin that can cause PD.
It must be converted to MPP+ by MAOb before it can exert its toxic effects.
Selective MAOb inhibitor reduces oxidative stress.

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24
Q

Where is a membrane-bound form of COMT localised?

A

Catecholaminergic synapses.

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25
Q

What are the two main effects of COMT inhibitors?

A

Increase levels of dopamine and noradrenaline in synapses.
Prolong dopamine receptor activation.

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26
Q

Generally, COMT plays a smaller role in the catabolism of catecholamines compared to DATs. Where in the brain does COMT play a larger role and why?

A

Prefrontal cortex.
DAT is expressed at relatively low levels, so COMT may play a larger role.

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27
Q

Mutations in COMT may be associated with what?

A

Cognitive dysfunction.
Risk of psychiatric disorders.

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28
Q

Name the two dopamine (DA) receptor families.

A

D1-like.
D2-like.

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29
Q

Which two DA receptors belong to the D1-like family?

A

D1.
D5.

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30
Q

Which three DA receptors belong to the D2-like family?

A

D2.
D3.
D4.

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31
Q

How do the D1-like and D2-like DA receptor families differ structurally?

A

D1-like = long intracellular carboxy-terminal loop.
D2-like = large third intracellular loop.

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32
Q

What is the main role of D1-like DA receptors?

A

Stimulate the formation of cAMP and activation of protein kinase A (PKA).

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33
Q

What are the two main roles of D2-like DA receptors?

A

Decrease cAMP formation.
Modulate potassium and calcium ion currents.

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34
Q

What type of receptor are DA receptors?

A

GPCR.

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35
Q

Which G-proteins can D1-like DA receptors be coupled to?

A

Gaolf (G-alpha-olf).
Gas (G-alpha-s).

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36
Q

How do D1-like DA receptors affect excitability?

A

Increase excitability.

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37
Q

How do D2-like DA receptors affect excitability?

A

Decrease excitability.

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38
Q

What is an important target of D1-like DA receptors?

A

Dopamine- and cAMP-regulated phosphoprotein of 32 kD (DARPP-32).

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39
Q

How do D1-like DA receptors amplify the PKA signal?

A

Inhibiting protein phosphatase 1 (PP1).

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40
Q

How do D1-like DA receptors affect potassium and calcium channels?

A

Inhibits voltage-gated potassium channels.
Inhibits inwardly-rectifying potassium channels (Kir).
Increases Cav1 (L-type) calcium channel currents.

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41
Q

Which G-protein are D2-like DA receptors coupled to?

A

Gai/o (G-alpha-i/o).

42
Q

Which pathway do D2-like DA receptors inhibit?

A

AC-cAMP-PKA transduction pathway.

43
Q

How do D2-like DA receptors affect potassium and calcium channels?

A

Activate inwardly-rectifying potassium channels (Kir).
Inhibit Cav1 (L) and Cav2.2 (N) channels.
Via membrane interactions of their Gby dimers.

44
Q

What type of complex can D1-like and D2-like DA receptors form with each other?

A

Heteromeric complex.

45
Q

D1/D2 heteromers are linked to what?

A

Calcium signalling via coupling with Gq and phospholipase C (PLC) transduction pathways.

46
Q

What are psychomotor stimulants also known as?

A

Indirect dopamine agonists.

47
Q

Why are psychomotor stimulants used to treat ADHD?

A

They block DAT or reverse its actions.

48
Q

Describe the action of antipsychotic drugs.

A

Block D2 receptors in subcortical structures in the limbic forebrain.

49
Q

Which two DA agonists are used to treat PD?

A

D2 agonists.
D3 agonists.

50
Q

How are the cell bodies of dopaminergic neurons organised?

A

Into discrete clusters.

51
Q

How are the cell bodies of dopaminergic neurons classified?

A

Alphanumerically into groups A8-A16.

52
Q

Name the four major dopaminergic pathways.

A

Nigrostriatal.
Mesocortical.
Mesolimbic.
Tuberoinfundibular.

53
Q

What is the nigrostriatal pathway involved in?

A

Motor planning.
Purposeful, voluntary movement.

54
Q

What is the mesocortical pathway involved in?

A

Physiology of cognition and executive function.
Emotions and affect.

55
Q

What is the mesolimbic pathway involved in?

A

Reward.
Incentive salience.
Pleasure.
Positive reinforcement.

56
Q

What is the tuberoinfundibular pathway involved in?

A

Hormone regulation, mainly prolactin secretion.

57
Q

Why does the substantia nigra appear dark in healthy (non-PD) individuals?

A

High neuromelanin content that forms from the L-dopa precursor in DA synthesis.

58
Q

Describe the nigrostriatal pathway in a healthy (non-PD) individual.

A

Axonal fibres projected by A9 dopaminergic neurons in the substantia nigra innervate the striatum to provide the DA needed for proper regulation of the motor circuit.

59
Q

Describe the nigrostriatal pathway in PD.

A

There is a significant loss of A9 dopaminergic neurons and degeneration of nigrostriatal fibres, leading to denervation of the striatum and depletion of its DA input.

60
Q

What is the DA hypothesis for schizophrenia?

A

A dysfunctional midbrain dopaminergic system may play an important role in the cause of schizophrenia.

61
Q

What is the evidence for the DA hypothesis for schizophrenia?

A

Amphetamine and cocaine increase DA levels, and their abuse can lead to psychosis.
Amphetamine exacerbates psychosis in schizophrenics.
PD patients taking L-DOPA sometimes show psychosis.

62
Q

Name three positive symptoms of schizophrenia.

A

Hallucinations.
Disorganised speech.
Erratic behaviour.

63
Q

Name three negative symptoms of schizophrenia.

A

Reduced expression of emotions.
Poverty of speech.
Social withdrawal.

64
Q

Name three cognitive symptoms of schizophrenia.

A

Impaired executive function.
Impaired working memory.
Difficulty initiating goal-directed behaviour.

65
Q

Which pathway of the midbrain dopaminergic system is thought to be involved in the expression of the positive symptoms of schizophrenia?

A

Overactivity of the mesolimbic pathway.

66
Q

Which pathway of the midbrain dopaminergic system is thought to be involved in the expression of the negative and cognitive symptoms of schizophrenia?

A

Dysfunction of the mesocortical pathway.

67
Q

Working memory requires which brain area?

A

The prefrontal cortex, specially the dorsolateral prefrontal cortex (DLPFC).

68
Q

What can impair working memory?

A

Depletion of prefrontal cortex DA or blocking D1 receptors.

69
Q

What is thought to underlie brain stimulation reward?

A

Projections from the VTA to the nucleus accumbens.

70
Q

All addictive drugs activate which DA system?

A

Mesocorticolimbic.

71
Q

Which three types of “reward” have been shown to increase extracellular levels of DA in the nucleus accumbens?

A

Natural reward, e.g. food.
Electrical self-stimulation.
Systemic administration of drugs of abuse.

72
Q

The tuberoinfundibular pathway transmits DA from where to where?

A

From the hypothalamus to the pituitary gland.

73
Q

In the tuberoinfundibular pathway, blocking D2-like DA receptors can result in what?

A

Increase in the plasma levels of prolactin.

74
Q

What can an increase in the plasma levels of prolactin lead to?

A

Gynaecomastia = enlargement of breast tissue in both sexes.
Galactorrhoea = milky discharge from the nipples, unrelated to normal lactation, in both sexes.

75
Q

Where is noradrenaline synthesised?

A

Synaptic vesicles.

76
Q

How is DA converted into NA?

A

A hydroxyl group is added to DA by dopamine beta-hydroxylase (DBH).

77
Q

Which three main actions does NA regulate?

A

Attention.
Impulsivity.
Autonomic function.

78
Q

Where is adrenaline synthesised?

A

In the axon terminal.

79
Q

How is adrenaline synthesised from NA?

A

Phentolamine N-methyltransferase (PNMT) adds a methane group to NA.

80
Q

What are the three main effects of adrenaline on the PNS?

A

Increases heart rate.
Constricts blood vessels.
Relaxes airways.

81
Q

Which transporter pumps adrenaline into synaptic vesicles?

A

Vesicular monoamine transporter (VMAT).

82
Q

In which neurons does adrenaline occur?

A

A small number of central neurons, all located in the medulla.

83
Q

What is the rate limiting enzyme for the production of NA and adrenaline, and why?

A

Tyrosine hydroxylase.
Both NA and adrenaline are synthesised from DA, and TH is the rate limiting enzyme for DA synthesis.

84
Q

Which transporter is responsible for the reuptake of NA into the terminal?

A

Noradrenaline transporter (NAT).

85
Q

Which two enzymes break down NA and adrenaline?

A

MAO.
COMT.

86
Q

Which branch of the nervous system do most adrenergic drugs target?

A

ANS.

87
Q

True or false: adrenaline and NA use the same receptors?

A

True.

88
Q

Are adrenoreceptors ionotropic or metabotropic?

A

Metabotropic.

89
Q

Name the five adrenoreceptor subtypes.

A

a1 (alpha-1).
a2.
B1 (beta-1).
B2.
B3.

90
Q

Which adrenoreceptor subtypes are postsynaptic noradrenergic receptors?

A

a1.
B1.
B2.
B3.

91
Q

Are postsynaptic noradrenergic receptors excitatory or inhibitory?

A

Excitatory.

92
Q

Which adrenoreceptor subtype is a presynaptic autoreceptor?

A

a2.

93
Q

Is the presynaptic a2 autoreceptor excitatory or inhibitory?

A

Inhibitory.

94
Q

Do all subfamilies of adrenoreceptors couple to the same G-protein?

A

No. Each subfamily preferentially couples to a different type of G-protein.

95
Q

How does the presynaptic a2 autoreceptor function in a negative feedback loop to modulate signalling between neurons?

A

Release of NA into synaptic cleft causes diffusion of transmitter and activates presynaptic a2 autoreceptor.
This inhibits further synthesis of NA and blocks the release of more transmitter.

96
Q

Name four NA-dependent functions.

A

Attention focusing and shifting.
Memory formation.
Stress response and mood regulation.
Sleep-wake cycle and circadian rhythm.

97
Q

Which region of the brain is vital in the regulation of sleep, arousal and attention?

A

Locus coeruleus (LC).

98
Q

How is the LC involved in anxiety?

A

In response to threat, LC firing may increase anxiety by releasing NA in the amygdala and other regions of the limbic forebrain.

99
Q

Why are beta-adrenergic receptor antagonists being investigated as interventions to decrease the intensity of traumatic memories in PTSD?

A

Stimulation of beta-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion.
This facilitates the recall of stimuli that predict danger.

100
Q

Where are the cell bodies of noradrenergic neurons found?

A

In the LC.

101
Q

Which four areas do ascending LC projections innervate?

A

Hypothalamus.
Amygdala.
Hippocampus.
Cortex.

102
Q

Which three areas do descending LC projections innervate?

A

Periaqueductal grey.
Other brainstem nuclei.
Spinal cord.

Cellular Neuroscience (10 decks)

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