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Neuroscience Y2S2 > Neurobiology of Disease 3 > Flashcards

Neurobiology of Disease 3 Flashcards

1
Q

Out of neurodegerative and psychiatric illnesses, which one primarily features apoptosis or loss of neurones? (1)

A

Neurodegenerative

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2
Q

Out of neurodegerative and psychiatric illnesses, which one primarily features developmental defects? (1)

A

Psychiatric

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3
Q

Out of neurodegerative and psychiatric illnesses, which one shows changes in behaviour? (1)

A

Both can show changes in behaviour

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4
Q

Where is the pathology in upper motor neurone disorders? (1)

A

CNS or spinal cord

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5
Q

Give three examples of upper motor neurone disorders. (3)

A
  • Stroke
  • Multiple sclerosis
  • ALS
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6
Q

Where is the pathology in lower motor neurone disorders? (1)

A

Outside the CNS

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7
Q

Give two examples of lower motor neurone disorders. (2)

A

Peripheral neuropathy

Myasthenia gravis

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8
Q

Where is the pathology usually situated in involuntary movement disorders? (1)

A

Basal ganglia

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9
Q

Give a common cerebellar pathology causing motor dysfunction. (1)

A

Tumour

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10
Q

Give three examples of involuntary movement disorders. (3)

A
  • Parkinson’s disease
  • Huntington’s disease
  • Tremor
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11
Q

Is Parkinson’s disease neurodegenerative, developmental, or psychiatric? (1)

A

Neurodegenerative

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12
Q

At what age is Parkinson’s disease classed as early onset? (1)

A

40-60yrs

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13
Q

Is early onset Parkinson’s disease usually caused by…

a) genetic mutations

b) environmental factors

A

a) genetic mutations

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14
Q

Is early onset or late onset PD more prevalent? (1)

A

Late onset

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15
Q

At what age is Parkinson’s disease classed as late onset? (1)

A

> 85yrs

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16
Q

Is late onset PD usually caused by…

a) genetic mutations

b) environmental factors

A

Combination of both

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17
Q

Is PD more common in males or females? (1)

A

Males

(3:2 ratio)

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18
Q

Give five motor symptoms of Parkinson’s disease. (5)

A
  • Slow movement (bradykinesia)
  • Postural abnormalities (eg. rigid posture)
  • Lack or rigidity of movement (akinesia)
  • Mask-like expression
  • Resting tremor
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19
Q

Give two psychological/cognitive symptoms of PD often seen in later stages. (2)

A
  • Depression
  • Dementia
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20
Q

Why is endocrine dysfunction often seen in Parkinson’s disease? (1)

A

Due to changes in the dopaminergic tuberoinfundibular pathway

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21
Q

Briefly describe the pathophysiology of Parkinson’s disease. (1)

A

Neurodegeneration of the extrapyramidal system (including the basal ganglia) due to loss of dopaminergic neurones in the substantia nigra.

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22
Q

Give three cellular mechanisms by which dopaminergic neurones in the substantia nigra may die in Parkinson’s disease. (3)

A
  • Oxidative stress
  • Mitochondrial dysfunction
  • Proteosome dysfunction
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23
Q

Name the dopaminergic pathway which is disrupted in Parkinson’s disease. (1)

A

Nigrostriatal pathway

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24
Q

Complete the sentence relating to Parkinson’s disease. (2)

In PD, there is loss of ………………. neurones of the substantia nigra, resulting in less DA input to the ……………. of the basal ganglia.

A

dopaminergic

(dorsal) striatum

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25
Q

Describe the changes seen in brain slices of PD patients. (1)

A

Loss of pigmented neurones in substantia nigra pars compacta.

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26
Q

Name the pigment which normally makes the substantia nigra appear dark. (1)

A

Neuromelanin

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27
Q

Apart from the substantia nigra, name another brain area where large quantities of neuromelanin are found. (1)

A

Locus coeruleus

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28
Q

Briefly describe 5 neurotransmitter changes seen in Parkinson’s disease. (5)

Relate these to the brain areas where they are seen.

A
  • Reduced DA in striatum
  • Reduced DA in mesolimbic areas
  • Reduced hypothalamic amines
  • Reduced cortical noradrenaline and ACh
  • Reduced neuropeptides (substance P) in striatum (and maybe also spinal neurones and interneurones)
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29
Q

What percentage reduction in dopaminergic neurotransmission to the striatum is required before motor symptoms are seen? (1)

A

60-70%

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30
Q

What effects are seen in Parkinson’s disease due to loss of dopamine in mesolimbic areas? (1)

A

Mood changes

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31
Q

What effects are seen in Parkinson’s disease due to loss of hypothalamic amines? (1)

A

Endocrine dysfunction

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32
Q

What effects are seen in Parkinson’s disease due to reduced cortical noradrenaline and ACh? (1)

A

Reduced cognition

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33
Q

What effects are seen in Parkinson’s disease which may be due to reduced neuropeptides in the striatum? (1)

A

Motor symptoms

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34
Q

Name a protein which is implicated in Parkinson’s disease. (1)

A

alpha-synuclein

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35
Q

Are a-synuclein aggregates causal or consequential of Parkinson’s disease? (1)

A

It is currently unknown

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36
Q

Describe the three components of the a-synuclein protein. (3)

A
  • N-terminal
  • Hydrophobic NAC region
  • Acidic C-terminal
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37
Q

What is the function of the N-terminal of the a-synuclein protein? (1)

A

Interacts with membrane lipids

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38
Q

What is the function of the hydrophobic NAC region of the a-synuclein protein? (1)

A

Relevant for aggregation

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39
Q

What is the function of the acidic C-terminal of the a-synuclein protein? (1)

A

Involved in calcium binding

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40
Q

Very briefly describe (4 words) the normal role of the a-synuclein protein in cells. (1)

A

Synaptic function and exocytosis

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41
Q

Briefly describe the cascade of a-synuclein forming cytotoxic aggregates in cells. (6)

A
  • Monomers (membrane-bound or free; can also be dimeric or tetrameric)
  • Misfolding and/or hyperphosphorylation
  • Oligomer
  • Protofibrils
  • Fibrils
  • Lewy body
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42
Q

What is the structure called when the a-synuclein proteins aggregate? (1)

A

Lewy bodies

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43
Q

Very briefly, how do lewy bodies cause cell death? (2)

A
  • They are cytotoxic
  • They are unable to perform their normal functions
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44
Q

As well as motor dysfunction, what other aspect of PD might Lewy bodies contribute to? (1)

A

Dementia

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45
Q

Describe five normal, physiological roles of the alpha-synuclein protein in dopaminergic terminals at rest. (5)

A
  • Inhibits DA synthesis (decreases TH phosphorylation)
  • Aids in sequestration of cytosolic DA (increases amount of VMAT on vesicles)
  • Prevents NT release through interactions with synaptic vesicles and SNARE proteins (prevents trafficking and docking)
  • Facilitates recycling of synaptic vesicles by mediating membrane bending during endocytosis
  • Maintains number of vesicles
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46
Q

Describe three normal, physiological roles of the alpha-synuclein protein in dopaminergic terminals during an action potential. (3)

A
  • Following Ca influx, a-synuclein rapidly disperses from terminal
  • Unimpeded vesicular trafficking and exocytosis
  • Disinhibited TH and AADC, so DA can be replenished
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47
Q

Why does influx of calcium during an action potential cause alpha-synuclein to disengage from the membrane and disperse? (1)

A

Because alpha-synuclein interacts with the membrane in a calcium dependent manner.

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48
Q

Describe the effects that the loss of a-synuclein function has on dopaminergic axon terminals in Parkinson’s disease. (5)

A
  • Increased DA synthesis (disinhibited TH and AADC)
  • Decrease in VMAT levels
  • Unregulated trafficking of synaptic vesicles
  • Impaired endocytic vesicular recycling
  • Decrease in size of vesicular pool
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49
Q

Describe how the distribution of dopamine in axon terminals is altered due to a-synuclein dysfunction in Parkinson’s disease. (2)

A

Increased cytosolic DA

with a reduction in DA in synaptic vesicles.

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50
Q

How does the increased cytosolic DA seen in Parkinson’s disease cause cell death? (3)

A
  • DA auto-oxidises
  • To produce reactive oxygen species
  • And DA quinones
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51
Q

What would be the result of using miRNA to silence a-synuclein in neurones? (1)

A

Neurodegeneration

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52
Q

What does colocalisation suggest about the relationship between alpha-synuclein and glutamate in Parkinson’s disease? (1)

A

They are colocalised, suggesting that a-synuclein may be involved in glutamatergic neurotransmission, and therefore in PD, a-synuclein may alter glutamatergic function as well as DA function.

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53
Q

At the Drosophila NMJ, glutamate acts as the excitatory neurotransmission.

What is the effect of overexpressing a-synuclein at the Drosophila NMJ? (1)

What does this suggest about a-synuclein and how it affects glutamatergic function? (2)

A

Larger mEJP (miniature excitatory junctional potential)

Suggesting that a-synuclein may help to package glutamate into vesicles

Because overexpression results in more glutamate per vesicle

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54
Q

Briefly describe the proposed effects of a-synuclein on dopaminergic and glutamatergic activity. (2)

A

Hypodopaminergic activity

Hyperglutamatergic activity

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55
Q

The effects of a-synuclein on glutamate in Parkinson’s disease may be complicated.

Give two ways by which a-synuclein is proposed to increase glutamatergic neurotransmission. (2)

A
  • Increase glutamate release from astrocytes
  • Excessive activation of NMDARs on postsynaptic neurones
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56
Q

How could Parkinson’s disease be diagnosed using PET/SPECT imaging? (3)

A
  • Use radioligand (CIT, cocaine analogue)
  • Binds to presynaptic DAT
  • Will see reduced signal
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57
Q

Explain why, during PET/SPECT imaging for Parkinson’s disease, using a DAT ligand would show a reduced signal but using a D2 ligand would not. (2)

A

Reduced DAT due to loss of dopaminergic neurones

however D2 found on postsynaptic neurones, which remain relatively unchanged.

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58
Q

What percentage of patients with PD have a first degree relative with PD? (1)

A

15%

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59
Q

Familial early onset Parkinson’s disease accounts for what percentage of PD cases? (1)

A

10-20%

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60
Q

Name five loci/genes which may be a risk factor for Parkinson’s disease. (5)

A

PARK1

PARK2

PARK4

PARK6

PARK7

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61
Q

Mutations in the PARK1 gene may play a role in Parkinson’s disease.

What protein does this gene encode? (1)

A

SNCA (a-synuclein)

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62
Q

Mutations in the PARK1 gene may play a role in Parkinson’s disease.

What phenotype is typically seen with mutations in this gene? (3)

A

Early onset PD

with Lewy bodies

and marked rigidity

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63
Q

Mutations in the PARK1 gene may play a role in Parkinson’s disease.

Give five mutations in this gene which confer risk for PD. (5)

A

A53T

A30P

E46K

H50Q

G15D

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64
Q

Mutations in the PARK1 gene may play a role in Parkinson’s disease.

PARK1 encodes the protein alpha-synuclein.

Name another loci/gene which encodes alpha-synuclein which may confer risk of PD. (1)

A

PARK4

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65
Q

PARK1 and PARK4 genes both encode a-synuclein and confer risk of PD.

What is the difference between the PARK4 and PARK1 genes? (2)

A

Different alleles

PARK4 is a triplication of the gene

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66
Q

Mutations in the PARK2 gene may play a role in Parkinson’s disease.

What protein is encoded by PARK2? (1)

A

Parkin

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67
Q

Mutations in the PARK1 gene may play a role in Parkinson’s disease.

What is the inheritance pattern of PARK1 mutations in PD? (1)

A

Autosomal dominant

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68
Q

Mutations in the PARK2 gene may play a role in Parkinson’s disease.

PARK2 encodes Parkin protein.

What is the role of the Parkin protein? (4)

A

Part of a ubiquitin proteasome

And acts as a protease

to regulate mitochondrial quality

through mitophagy and mitochondrial biogenesis.

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69
Q

Mutations in the PARK2 gene may play a role in Parkinson’s disease.

What is the inheritance pattern of PARK2 mutations in PD? (1)

A

Autosomal recessive

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70
Q

Mutations in the PARK2 gene may play a role in Parkinson’s disease.

Describe the PD phenotype seen in patients with PARK2 mutations. (3)

A

Early onset PD

restricted to SN cell loss

without Lewy bodies

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71
Q

Mutations in the PARK6 gene may play a role in Parkinson’s disease.

Which protein is encoded by PARK6? (1)

A

PINK-1

(PTEN-induced kinase-1)

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72
Q

Mutations in the PARK6 gene may play a role in Parkinson’s disease.

What is the inheritance pattern of PARK6 in PD? (1)

A

Autosomal recessive

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73
Q

Mutations in the PARK6 gene may play a role in Parkinson’s disease.

PARK6 encodes PINK-1 protein.

What is the role of PINK-1 protein? (3)

A

Mitochondrial serine/threonine protein-kinase

which recruits parkin to depolarised mitochondria

for mitophagy

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74
Q

Mutations in the PARK7 gene may play a role in Parkinson’s disease.

What protein does PARK7 encode? (1)

A

DJ-1

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75
Q

Mutations in the PARK7 gene may play a role in Parkinson’s disease.

What is the inheritance pattern of the PARK7 mutation in PD? (1)

A

Autosomal recessive

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76
Q

Mutations in the PARK7 gene may play a role in Parkinson’s disease.

PARK7 encodes the DJ-1 protein.

What is the role of this protein? (2)

A

Involved in oxidative stress response

and mitochondrial function.

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77
Q

Give two genes which increase risk of sporadic Parkinsonism. (2)

A

Leucine-rich repeat kinase 2 (LRRK2)

SNCA

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78
Q

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

Sporadic Parkinsonism tends to occur without family history or gene mutations.

A

False -

It does tend to occur without family history

However can occur due to multiple gene alterations with influence risk factor susceptibility to PD

79
Q

Give two environmental risk factors for Parkinson’s disease. (2)

A
  • MPTP (drug-induced neurodegeneration)
  • Paraquat/rotenone (exposure to herbicide)
80
Q

Describe how MPTP may cause PD. (4)

A
  • Converted to MPP
  • By monoamine oxidase B in astrocytes
  • Taken up into DA neurones by DAT
  • Acts as a mitochondrial toxin
81
Q

Briefly describe how herbicides can cause PD. (2)

A
  • Taken up by DA neurones via DAT (or diffuse across membrane)
  • Cause oxidative stress
82
Q

Complete the passage relating to PD risk factors. (3)

Genetic factors are thought to primarily affect ……………… and ………………….. function.

However environmental factors predominantly affect …………………… function.

A

synaptic

mitochondrial

mitochondrial

83
Q

Name a type of therapeutic drug which causes Parkinsonism. (1)

A

Antipsychotics/neuroleptics

84
Q

Name a potential target for treatment in Parkinson’s disease. (1)

A

Postsynaptic DA receptors

85
Q

Why can’t dopamine be used to treat PD? (1)

A

Cannot cross BBB

86
Q

Why can’t L-DOPA be used alone to treat Parkinson’s disease? (1)

A

It would be converted to dopamine in the periphery, and dopamine cannot cross the BBB.

87
Q

What is the most common treatment for Parkinson’s disease? (1)

A

Levodopa (a dopamine precursor)

+

Carbidopa (peripheral DOPA decarboxylase inhibitor)

88
Q

Describe how levodopa + carbidopa is effective in PD. (4)

A

Carbidopa inhibits DOPA decarboxylase outside CNS

Levodopa crosses BBB

Converted to dopamine in decarboxylase-positive neurones

So increased DA neurotransmission in the CNS

89
Q

In addition to not being able to cross the BBB and act in the CNS, give another reason why dopamine should not be applied systemically. (1)

A

It can be converted to noradrenaline/adrenaline and act systemically.

90
Q

Give five unwanted side effects of long-term levodopa+carbidopa use in PD. (5)

A
  • Chorea and involuntary movements
  • Rapid fluctuation of clinical states (on-off effect)
  • Nausea and anorexia
  • Hypotension
  • Psychotic effects
91
Q

When does development of chorea and involuntary movements usually occur in PD treatment? (1)

A

After about 2yrs of use

92
Q

Why are nausea and anorexia often seen in PD treatment? (1)

A

Due to peripheral drug effects

93
Q

Why are psychotic effects often seen as a side-effect of PD treatment? (1)

A

Due to changes in the mesocortical/mesolimbic pathways pathways

94
Q

In order of earliest effects to later effects, describe how the efficacy of levodopa/carbidopa therapy changes over time in PD. (5)

A
  • Excellent control
  • End of dose ‘wearing off’
  • Fluctuations (on-off effect)
  • Dyskinesias
  • Loss of control
95
Q

How long after diagnosis of PD is death likely to occur? (1)

A

10-15yrs

96
Q

Suggest 6 alternative therapeutic strategies (apart from levodopa) in PD treatment. (6)

A
  • D2 receptor agonists
  • Monoamine oxidase B inhibitors
  • Catechol-O-methyl transferase inhibitors
  • Increase DA release from nerve terminals
  • Adenosine A2a receptor antagonist
  • Muscarinic receptor antagonists
97
Q

In which subset of PD patients are D2 receptor agonists more likely to be used? (1)

A

Early onset

98
Q

Give two examples of D2 receptor agonists which can be used to treat PD. (2)

A
  • Ropinirole
  • Bromocriptine
99
Q

Give an example of a MAOB inhibitor that can be used to treat PD. (1)

A

Selegiline

100
Q

Give a condition that must be met for COMT inhibitors to be effective in PD treatment. (1)

A

Must be used with L-DOPA

101
Q

Give two examples of COMT inhibitors that can be used to treat PD. (2)

A
  • Tolcapone
  • Entacapone
102
Q

Which receptor/receptors do D2 receptor agonists bind to in order to treat PD? (1)

A

D2
D3
D4

103
Q

When are adenosine A2a antagonists used to treat PD? (1)

A

As add-on therapy with L-DOPA

104
Q

Give a medication that treats PD by increasing DA release from nerve terminals. (1)

By what mechanism does this drug work? (1)

A

Amantadine

Mechanism not really known

105
Q

What specific symptom of Parkinson’s disease may be helped by muscarinic receptor antagonists? (1)

A

Tremor

106
Q

Apart from drugs, give three other techniques that may potentially be used to treat Parkinson’s disease. (3)

A
  • Stem cell transplant
  • Promotion of neuronal survival and reinnervation
  • Blockade of a-synuclein aggregation
107
Q

How might neuronal survival and reinnervation be promoted in PD treatment? (1)

A

Nicotinic receptor agonists

108
Q

Name the brain pathway which seems to be most involved in addiction and reward. (1)

A

Mesolimbic dopamine pathway

109
Q

In addition to dopaminergic neurotransmission, name another type of neurotransmission which innervates the nucleus accumbens. (1)

A

Serotonergic

110
Q

Briefly describe an experimental setup to test the activity of VTA neurones in reward and reward prediction. (4)

HINT: This is done in mice/rats

A
  • Rodent in box with lever to deliver reward
  • Lever press delivers IV cocaine
  • Microelectrodes able to record VTA activity
  • Can manipulate size of reward (ie. amount of cocaine) to test reward prediction error
111
Q

In a rodent test where rewards are self-administered and VTA neuronal activity is recorded, describe what you would expect to see and what the effects of this are if the reward is unpredicted. (3)

A
  • Phasic, short-lasting burst of activity in VTA neurones
  • This results in DA release from nerve terminals
  • In the nucleus accumbens and frontal cortex
112
Q

In a rodent test where rewards are self-administered and VTA neuronal activity is recorded, describe what you would expect to see and what the effects of this are if the reward is better than predicted. (2)

What is this response called? (1)

A

Stronger neuronal response elicited

resulting in more DA release

Positive prediction error response

113
Q

In a rodent test where rewards are self-administered and VTA neuronal activity is recorded, describe what you would expect to see and what the effects of this are if the reward is worse than predicted. (2)

What is this response called? (1)

A

Decrease in neuronal firing

Less DA release

Negative prediction error response

114
Q

In a rodent test where rewards are self-administered and VTA neuronal activity is recorded, describe what you would expect to see and what the effects of this are if the reward is fully and accurately predicted. (2)

A

No response by the neurones

so no change in DA

115
Q

How does the dopamine reward prediction error contribute to learning? (1)

A

The dopamine response to a reward (outcome) changes prediction for the future.

116
Q

Describe how the dopaminergic response to reward and the reward prediction error may contribute to addiction. (4)

A
  • Body doesn’t experience as strong a reward to drug as what is expected
  • Perhaps due to tolerance
  • Negative DA response (and negative feeling) will be elicited
  • So person increases dose to try and increase DA response
117
Q

Name a technique that can be used in rodents to measure ECF levels of neurotransmitter during activity. (1)

A

Microdialysis

118
Q

Briefly describe how microdialysis would enable measurement of dopamine and serotonin levels in the brain in response to a reward (in rodents). (4)

A
  • Probe implanted with semi-permeable membrane
  • Perfused with artificial CSF
  • NTs transfuse from brain parenchyma to inside the probe with aCSF
  • Can analyse the dialysate and measure levels of NT
119
Q

What is an advantage of using Drosophila to investigate reward and learning pathways instead of rodents or humans. (1)

A

There are less neurones present so they are easier to identify and map.

120
Q

Briefly describe an experimental setup which would allow investigation of reward and learning pathways in Drosophila larvae. (4)

A
  • Train larvae to associate specific smell with reward (eg. fructose food medium)
  • Give non-rewarding food with a different smell
  • In test, have both smells present and count how many larvae go towards the rewarding smell
  • This can be done with genetic knockouts of specific receptors or pathways
121
Q

Name the brain region in Drosophila where reward and learning are thought to interact with each other. (1)

What neurotransmitter is involved in this? (1)

A

Mushroom body

Dopamine

122
Q

Give the three general targets/brain changes of drugs of abuse. (3)

A
  • Increase DA in nucleus accumbens
  • Enhance serotonergic function (potentially in nucleus accumbens)
  • Block NMDA receptors
123
Q

Give nine drugs of abuse which act by increasing dopamine in the nucleus accumbens. (9)

A
  • Opiates/Opioids
  • Nicotine
  • Amphetamine
  • Cocaine
  • Ethanol
  • Cannabis
  • Cathinones (amphetamine-like)
  • Barbiturates
  • Caffeine
124
Q

Give two drugs of abuse which may act by enhancing serotonergic function (potentially in nucleus accumbens). (2)

A
  • LSD
  • Ecstasy (MDMA)
125
Q

Give two drugs of abuse which may act by blocking NMDA receptors. (2)

A
  • Phencyclidine (PCP)
  • Ketamine
126
Q

Drugs of abuse which act by blocking NMDA receptors produce what effects? (2)

A
  • Hallucinations
  • Delusions
127
Q

How does cocaine enhance dopaminergic neurotransmission? (2)

A

Indirect agonist at dopamine receptors

by inhibiting dopamine reuptake transporters

128
Q

How do amphetamines and amphetamine-related drugs of abuse enhance dopaminergic neurotransmission? (2)

A

Indirect agonist at dopamine receptors

by stimulating dopamine release

129
Q

Complete the passage relating to drugs of abuse. (2)

In general, drugs of abuse tend to increase dopamine levels, predominantly in the ………………………… brain region, and in a ……………………..-dependent manner.

A

nucleus accumbens

dose

130
Q

Complete the passage relating to dopamine and drugs of abuse. (2)

The faster, higher, and more reliable the elevation in brain dopamine levels, the ………………… the reward (euphoria), and the ……………… likely it is for addiction to occur.

A

greater

more

131
Q

Give two properties of drugs of abuse which can affect the speed, level, and reliability of the dopamine elevation in the brain. (2)

A
  • Concentration of drug
  • Formulation and absorption rate of drug
132
Q

What is physical drug dependence and how does it relate to addiction? (1)

A

Physical drug dependence is an altered physiological state produced by repeated drug administration.

Dependence can often precede addiction.

133
Q

Give four properties of a drug which can affect the physical dependence on it. (4)

A
  • Pharmacokinetics
  • Structure
  • Pathways
  • Receptor affinity
134
Q

Give four examples of drugs of abuse with very strong physical dependence. (4)

A
  • Morphine
  • Heroin
  • Cocaine
  • Nicotine
135
Q

Give four examples of drugs of abuse with very weak or absent physical dependence. (4)

A
  • Cannabis
  • Caffeine
  • Ecstasy (MDMA)
  • LSD
136
Q

Describe how GABAergic, glutamatergic, and dopaminergic neurones interact with each other to affect DA transmission from VTA to nucleus accumbens. (1)

A

GABAergic neurones usually inhibit VTA neurones

Glutamatergic input usually stimulates VTA neurones

137
Q

Give four effects of ethanol on GABAergic, glutamatergic, and dopaminergic neurones in the VTA/nucleus accumbens to increase dopaminergic neurotransmission. (4)

A
  • Directly increases firing rate of VTA neurones
  • Increases Ih and GIRK currents in VTA DA neurones to cause depolarisation
  • Decreases GABAergic inhibition of VTA neurones
  • Enhances glutamatergic synaptic strength (increased AMPA/NMDA ratio)
138
Q

Give three effects of nicotine on GABAergic, glutamatergic, and dopaminergic neurones in the VTA/nucleus accumbens to increase dopaminergic neurotransmission. (3)

A
  • Directly increases VTA cell firing
  • Increased excitatory glutamate release
  • HOWEVER also increases inhibition by GABAergic interneurones

(but there is an overall increase in DA)

139
Q

Give four drugs of abuse which directly increase DA concentration either at the synapse or by acting directly on VTA neurones. (4)

A
  • Cocaine
  • Ethanol
  • Nicotine
  • Amphetamine
140
Q

Describe two effects (one in more detail than the other) of morphine on GABAergic, glutamatergic, and dopaminergic neurones in the VTA/nucleus accumbens to increase dopaminergic neurotransmission. (3)

A
  • Activates MORs on GABAergic interneurones
  • Which results in a decrease in GABAergic cell firing and IPSP frequency
  • Also enhances glutamatergic synaptic strength (increased AMPA/NMDA)
141
Q

As well as cocaine acting directly at the synapse to increase DA, give an effect that it may have in the VTA on either dopaminergic, glutamatergic, or GABAergic neurones. (1)

A

Enhances glutamatergic synaptic strength (increases AMPA/NMDA ratio)

142
Q

Cannabinoids result in increased DA release in the nucleus accumbens.

Are cannabinoids thought to act directly on dopaminergic neurones in the VTA, or indirectly on GABAergic or glutamatergic neurones in the VTA to enhance dopamine? (1)

A

Indirect

143
Q

Describe the mechanism of how alcohol is able to enhance DA release from the VTA by decreasing GABAergic interneurone inhibition. (4)

A
  • Alcohol causes beta-endorphin release
  • Endorphins act on MORs of GABAergic interneurones
  • This results in the neurone being inhibited and less GABA release
  • So less inhibition of VTA neurones and more DA release
144
Q

Why is it important clinically to understand the pathway and cellular mechanism of how alcohol causes increased DA? (1)

A

Understanding this mechanism may allow new pharmacological approaches to treating alcohol addiction.

145
Q

How does the long-term use of drugs of abuse lead to long-term addiction? (4)

A

Alter gene expression

Due to dopamine binding to GPCRs

Affecting transcription factors and/or epigenetics

Which can then cause altered synaptic plasticity and attenuated reward to normal stimuli

146
Q

What is the difference between opiates and opioids? (2)

A

Opiates are natural substances

Opioids are man-made, synthetic forms

147
Q

Give four examples of opiates. (4)

A

Morphine

Heroin

Opium

Codeine

148
Q

Give two examples of opioids. (2)

A

Methadone

Fentanyl

149
Q

Complete the passage relating to opiates and opioids. (5)

Opiates and opioids are ……………….. at receptors (for example the u-opioid receptor, MOR).

These receptors are ………………………….

They act to ………………… neurotransmitter release.

They may do this by enhancing …………. channels and inhibiting ……………. channels.

HINTS:

1 is agonists/antagonists

2 is ligand-gated ion channels / GPCRs

3 is increase/reduce

4 and 5 are types of channels

A

agonists

GPCRs

reduce

K

Ca

150
Q

Give six acute effects of opiates/opioids. (6)

*This includes therapeutic, drugs of abuse, and side effects

A
  • Analgesia
  • Euphoria
  • Positive reinforcement
  • Tranquillity
  • Miosis (pupillary constriction)
  • Respiratory depression
151
Q

Give six chronic effects of opiates/opioids. (6)

A
  • Constipation
  • Depression
  • Insomnia
  • Dependence
  • Anhedonia
  • Tolerance
152
Q

Give five withdrawal effects of opiates/opioids. (5)

A
  • Craving
  • Restlessness
  • Insomnia
  • Diarrhoea
  • Cold flashes with goosebumps (‘cold turkey’)
153
Q

Describe the time course of opiate/opioid withdrawal symptoms. (2)

  • When do symptoms peak?
  • When do symptoms tend to subside?
A

Peak 24-72hrs after last dose

Subside after about a week

154
Q

What G protein is usually linked to opioid receptors? (1)

A

Gi

155
Q

Complete the sentence relating to cocaine. (2)

Cocaine is an …………. extracted from the ………………. (Erythroxylum coca).

A

Alkaloid

coca tree

156
Q

Give three formulations in which cocaine can be taken. (3)

A
  • Leaves chewed (in Peru)
  • Snorted
  • Smoked with tobacco
157
Q

In Peru, people chew cocaine leaves. What molecular form of cocaine does this produce? (1)

A

Cocaine hydrochloride

158
Q

Complete the sentence relating to cocaine. (4)

Crack cocaine is a form of cocaine known as a ……………………

Crack cocaine results in ……………….. tolerance, ………………… physical dependence, and ………………… psychological dependence.

A

Free base

Little

Little

Strong and rapid

159
Q

Give three effects of low dose cocaine. (3)

A

Euphoria

Excitement

Increased capacity for work

160
Q

As well as increasing dopamine, what other effects on neurotransmission can cocaine have at high doses? (2)

A

Blocks NA and adrenaline uptake

to cause overactivity of the sympathetic nervous system.

161
Q

Give four autonomic symptoms that can be caused by high dose cocaine. (4)

A

Hypertension

Tachycardia

Dilated pupils

Palpitations

162
Q

What is meant by ‘tolerance’? (1)

A

Higher doses required to maintain the same effect.

163
Q

Ki is the amount of a drug needed to inhibit a protein by a certain amount.

What would you expect to see if you compared the Ki for cocaine inhibiting DAT between people who regularly take cocaine, and people who have never taken cocaine? (1)

Explain what this means. (1)

A

Ki higher for people who regularly take cocaine

More cocaine needed for same DAT inhibition and DA increase in people who regularly take cocaine.

164
Q

Describe what you would expect to see in an experiment where:

the same dose of cocaine is given to a group of people who have never taken cocaine before and a group who regularly use cocaine, in terms of dopamine levels. (1)

What method of measuring DA levels would be used if this experiment was carried out in rodents? (1)

A

Larger rise in dopamine in cocaine-naive group

Microdialysis

165
Q

Complete the sentence relating to cannabis. (2)

Cannabis, or marijuana, refers to the various preparations of the ……………………….. plant, with ………………. as the active ingredient.

A

Cannabis sativa

THC (tetrahydro-cannabinol)

166
Q

The drug of abuse, cannabis, mimics the effects of endogenous endocannabinoids.

Give an example of an endogenous endocannabinoid. (1)

A

Anandamine

167
Q

Very briefly describe the mechanism of how cannabis works when used as a drug of abuse. (1)

A

Inhibits a wide range of neurotransmitters from being released in the brain and periphery.

168
Q

What types of receptors (ligand-gated ion channels or GPCRs) are cannabinoid receptors? (1)

A

GPCRs

169
Q

What G protein is coupled to cannabinoid receptors? (1)

A

Gi

170
Q

Name two types of cannabinoid receptors and describe their distributions in the body. (4)

A

CB1

CB2

CB1 found in CNS

CB2 largely peripheral

171
Q

What is the effect seen with a moderate dose of cannabis? (1)

A

Mild euphoric effect

172
Q

What is the effect usually seen with a high dose of cannabis? (1)

A

Dysphoric effect (particularly in naive users)

173
Q

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

Cannabis has an analgesic effect.

A

True

174
Q

How does cannabis stimulate appetite? (1)

A

It acts on feeding centres in the hypothalamus and possibly gut.

175
Q

Cannabis has a very low acute toxicity.

Describe what is meant by this. (1)

A

Not really any long-term effects from just using it once or for a short time.

176
Q

There are concerns about chronic heavy users of cannabis potentially developing what condition? (1)

A

Psychosis

177
Q

Very briefly describe the mechanism by which high dose cannabis is thought to increase dopamine. (1)

A

Inhibition of GABAergic VTA interneurones

178
Q

Anandamide, an endogenous endocannabinoid, is broken down by what enzyme? (1)

A

FAAH (fatty acid amide hydrolase)

179
Q

What would be the effect on dopamine levels if an FAAH (fatty acid amide hydrolase) inhibitor was given? (1)

Explain your answer. (3)

A

Increased dopamine

Because FAAH usually breaks down cannabinoids

So if an inhibitor is given the cannabinoids persist for longer

And cannabinoids increase DA release

180
Q

The endogenous endocannabinoid, anandamide, enhances DA release by acting on which receptor? (1)

A

CB1

181
Q

Give the general chemical name of the structure of amphetamine drugs. (1)

A

Phenylethylamine

182
Q

Give two examples of amphetamine drugs. (2)

A
  • Methamphetamine
  • Dexamphetamine
183
Q

Give 12 effects of taking amphetamines (as drugs as abuse). (12)

A
  • Increased wakefulness
  • Increased concentration
  • Decreased fatigue
  • Decreased appetite
  • Enhanced performance (eg. sport/war)
  • Euphoria
  • Increased self-esteem
  • Increased self-confidence
  • Aggression
  • Excessive feelings of power
  • Obsession
  • Paranoia
184
Q

Give five side effects of amphetamine drugs. (5)

A
  • Some degree of tolerance
  • Psychosis (with chronic use and/or high doses)
  • Increased cardiovascular tone
  • Raised blood pressure
  • Tachycardia
185
Q

Amphetamines increase synaptic levels of DA, NA, and 5HT.

Briefly explain two mechanisms as to how this happens. (2)

A
  • Releases monoamines from neuronal storage vesicles
  • Block DAT, NET, and SERT transporters
186
Q

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

Different isoforms of amphetamine (which all act via the same mechanism) all cause the same response profile (dose-response curve).

A

False - different isoforms cause different response profiles

187
Q

Which form of the drug amphetamine, is neurotoxic and can kill midbrain dopamine neurones? (1)

A

Methamphetamine

188
Q

PET scans using a ligand for the DAT transporter can be carried out in people who abuse drugs and in control groups.

What would you expect to see in people who abuse amphetamines regarding the DAT ligand binding in a PET scan? (2)

A

Decreased signal given off

due to decreased DAT levels.

189
Q

Ki is the concentration of a drug needed for 50% inhibition of a protein.

What is the relationship between Ki and affinity? (1)

A

Lower Ki means higher affinity

190
Q

Looking at the Ki of cocaine for NET, DAT, and SERT; which value would you expect to be the lowest? (1)

A

DAT

191
Q

Looking at the Ki of amphetamine for NET, DAT, and SERT; which value would you expect to be the lowest? (1)

A

NET

192
Q

What is the relationship between IC50 and drug binding affinity? (1)

A

Lower IC50 means higher affinity

193
Q

DAT/SERT binding ratio for a drug can be calculated from the IC50 values.

This can be used to predict potential for abuse.

Describe in words what is meant by the DAT/SERT ratio (giving an example of what a high or low ratio means). (1)

What is the relationship between DAT/SERT ratio and potential for drug abuse? (1)

A

Lower ratio means the drug binds more to SERT and inhibits SERT more than DAT.

Lower ratio = lower abuse potential

194
Q

The DAT/SERT ratio can be calculated for MDMA, amphetamine, and cocaine.

What do you expect the relative DAT/SERT ratios to be for these compounds, and which drugs have more potential for abuse? (2)

A

DAT/SERT ratios:

MDMA<cocaine<amphetamine

Potential for abuse:

MDMA<cocaine<amphetamine

Neuroscience Y2S2 (15 decks)

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