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Disease in the brain > Dopmaine pathways (finished) > Flashcards

Dopmaine pathways (finished) Flashcards

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1
Q

*

Describe the structure of dopamine

A

catechol ring= 6 carbons

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2
Q

What are catecholamines?

A

= group of neurotransmitters which includes dopamine, noradrenaline + adrenaline

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3
Q

When was dopamine synthesised?

A

1910

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4
Q

Who were the 1st people to synthesise dopamine?

A

George Barger and James Ewens

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5
Q

What are catecholamines derived from?

A

tyrosine

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6
Q

What was dopamine initally considered to be?

A

a precursor to noradrenaline (norepinephrine) and adrenaline (epinephrine) with no function of its own

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7
Q

When was dopamine established as a neurotransmitter?

A

1958 but Nobel Peace prize won for this in 2000

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8
Q

Who established dopamine as a neurotransmitter with a function?

A

Arvid Carlsson

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9
Q

Describe the synthesis of dopamine

A

Synthesised in 2 steps:

  1. tyrosine hydroxylase (TH) converts tyrosine into L-DOPA by adding hydroxyl group (OH) to backbone of tyrosine- L-DOPA has short lifetime so is further converted by…
  2. DOPA decarboxylase- converts L-DOPA rapidly into dopamine by removing carboxyl group
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10
Q

What is considered to be the rate limiting step in dopamine synthesis?

A

= tyrosine hydroxylase

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11
Q

What is the difference between the enzymes involved in dopamine synthesis?

A

Tyrosine hydroxylase = substrate specific- only converts tyrosine

DOPA decarboxylase = non substrate specific- so can convert any L amino acid

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12
Q

What is the rate of dopamine synthesis regulated by?

A

Catecholamines can inhibit tyrosine hydroxylase (TH) found in cytosol

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13
Q

Describe 2 reasons why synthesis of dopamine is altered

A
  • Presynaptic dopamine receptors (D2) inhibit synthesis and release of dopamine by activating signalling pathways- feedback inhibition which are negatively or positively coupled to cAMP signalling + Voltage gated calcium channels
  • Neuronal activity alters synthesis = levels of activity of neurons can change amount of dopamine produced- more activity = more dopamine produced
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14
Q

Name a co-factor of tyrosine hydroxylase

A

Tetrahydrobiopterin (BH4) = crucial for correct function of tyrosine hydroxylase

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15
Q

Name 2 dopamine transporter proteins

A

DAT
VMAT

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16
Q

What is the structure of DAT and where is it located?

A

12 transmembrane-spanning protein ~619 amino acids- located on- pre-synaptic membrane

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17
Q

What is the main function of DAT?

A

Takes up excess dopamine from synaptic cleft- known as a transporter

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18
Q

Name 3 drugs that bind to DAT + what does this result in?

A

= Binding site for cocaine, amphetamine and methylphenidate

FUNCTION = Block the transporter (= DAT) that would usually take up excess dopamine = inhibits reuptake so increase dopamine in the synaptic cleft = activates post-synaptic receptors = increased signalling

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19
Q

What is the main deactivation method used by DAT?

A

uses ion gradient created by the Na+/K+ ATPase- by coupling influx of sodium ions (= symporting ion) into cytosol, it also imports dopamine i.e. energy gradient created to move dopamine back into pre-synaptic neuron

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20
Q

What is the function of VMAT?

A

= packages vesicles with dopamine- transport dopamine from cytosol into vesicles

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21
Q

Describe the 2 differences between VMAT and DAT

A
  • VMAT has similar structure to DAT but small difference which determines if it is found in pre synaptic membrane (DAT) or the vesicular membrane (VMAT)
  • VMAT does not use Na+ as a symporting ion- instead uses hydrogen ions in presynaptic vesicles, they are pushed down their concentration gradients at same time dopamine is moved into synaptic vesicles
22
Q

What does reserpine do?

A

blocks VMAT-2 and depletes DA as it is not reintroduced into vesicles = Depletes all dopamine = results in Parkinsons

23
Q

What happens when the DAT gene is knocked out in animals?

A

elevates the synaptic level of DA in all brain regions with DA terminals – enhancing DA neurotransmission in the striatum results in these rats being hyperactive

24
Q

What is 6-hydroxydopamine?

A

(like dopamine but has + OH) – neurotoxin that is only taken up by DAT

25
Q

What does 6-OHDA do?

A

Inhibits mitochondrial respiratory chain leads to neuronal death
= causes oxidative stress = damages neurons:

  • Auto-oxidation produces hydrogen peroxide
  • = Causes oxidative stress to mitochondria releasing cytochrome c leading to death of dopamine and noradrenaline neurons
26
Q

What happens when 6-OHDA is injected into striatum of mice ?

A
  1. Induces oxidative stress in dopaminergic neurons
  2. = reduction in dopamine signalling
  3. = neurodegeneration by behavioural changes- Parkinsons
27
Q

Name the 2 enzymes that are responsible for the metabolism of dopamine

A

Monoamine oxidase (MAO)
COMT

28
Q

Where is MAO found?

A

On inner mitochondrial membrane in cells- e.g. neurons

29
Q

Where is COMT found?

A

Cytosol but also membrane bound

30
Q

Describe the role of COMT and MAO

A
  • Each produce an intermediate
    COMT produces 3-MT
    MAO produces DOPAC
  • Enzymes act in either order to produce common metabolite HVA = inactive molecule that is secreted out of the body
31
Q

What is the difference between dopaminergic, noradrenergic and adrenergic neurons?

A
  • Dopaminergic neurons = has tyrosine hydroxylade & DOPA decarboxylase
  • Noradrenergic neurons = also have dopamine b-hydroxylase
  • Adrenergic neurons (e.g. chromaffin cells in the adrenal medulla) = have PNMT on top of this
32
Q

Name the 5 subtypes of dopamine receptors and what do they all have in common?

A

= G-protein coupled receptors:
D1
D2
D3
D4
D5

33
Q

Name the D1 like dopamine receptors

A

D1 and D5

34
Q

Name the D2 like dopamine receptors

A

D2
D3
D4

35
Q

On which neuron is each dopamine receptor found?

A
  • D1 = Post-synaptic
  • D5 = Post-synaptic
  • D2= Pre- and Post-synaptic: Striatum high levels
  • D3 = Post-synaptic: Nucleus accumbens - VTA pathway Presynaptic in cortex?
  • D4 - Pre- and Post-synaptic: Frontal cortex, amygdala, hippocampus
36
Q

What is the main difference between D1 like receptors and D2 like receptors?

A

D1 = positively coupled to AC/cAMP signalling
D2 = negatively coupled to AC/cAMP signalling

37
Q

Compare the structure of D1 like receptors and D2 like receptors

A

D1 has long c terminal- D2 has short c terminal
In D2 there is a very large loop compared to D1

38
Q

Describe some different cellular downstream reponses in D1 and D2 receptors

A

D1 = more PIP hydrolysis, calcium is increased and PKC activation = excitability increased following activation of D1
D2 = increased potassium which hyperpolarises membrane, reduces calcium = excitability reduced following activation of D2

39
Q

How were dopamine neuronal pathways 1st established?

A

Falck – Hillarp Fluorescence 1960’s- wanted to look at brains were not necessarily looking for dopamine- to do this:
1. Freeze dried brain tissue to remove all water
2. Then exposed to formaldehyde vapor to dry it
But they observed that after exposure to formaldehyde = converted Dopamine to a fluorescent isoquinoline molecule that could be seen as a yellow green colour under the microscope

40
Q

What method was used to improve Falck-Hillarp fluoresence

A

1980s- tyrosine hydroxylase immunohistochemistry produced even better resolution of visualizing dopaminergic neurons e.g. generate antibody against tyrosine hydroxylase = can specifically stain neurons

41
Q

Name the 4 different dopamine pathways

A

Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular

42
Q

What % of neurons are dopaminergic?

A

1%

43
Q

Where do neurons originate and stretch to in the nigrostriatal pathway?

A

neurons originates in substantia nigra and stretches to striatum

44
Q

Where do neurons originate and stretch to in the mesolimbic pathway?

A

neurons originates in tegmentum / VTA and stretches to nucleus accumbens

45
Q

Where do neurons originate and stretch to in the mesocortical pathway?

A

neurons originate in tegmentum / VTA and stretches to frontal cortex

46
Q

Where do neurons originate and stretch to in the tuberinfundibular pathway?

A

small pathway- relates to hypothalamus
-arcuate nucleus of the hypothalamus innervate the median eminence in the anterior pituitary gland.

47
Q

What does the nigrostriatal pathway control for and what does degeneration of the neurons result in?

A

controls planning and execution of voluntary skeletal muscle movement.
- = Degeneration of these neurones occurs in Parkinson’s disease leading to motor impairment symptoms

48
Q

What does the mesolimbic pathway control for and what does overactivity of the neurons result in?

A

part of the limbic system controlling emotion, pleasure reward and goal-directed behaviour
- Over-activity in this pathway contributes to psychosis, delusions and hallucinations the positive symptoms of schizophrenia

49
Q

What does the mesocortical pathway control for and what does underactivity of the neurons result in?

A

neuronal activity is associated with emotion and motivation.
- Under-activity in this pathway may contribute to negative symptoms (social withdrawal/cognitive dysfunction) seen in schizophrenia.
- Cognitive side-effects sometimes known as ‘neuroleptic-induced deficit syndrome’ may also be mediated by this pathway.

50
Q

What does the tuberoinfundibular pathway control for?

A

Neuroendocrine associated pathway:
- DA release inhibits prolactin secretion; involved in maternal behaviour (neuroendocrine function).

Disease in the brain (22 decks)

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