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NHB > CNS Pharmacology > Flashcards

CNS Pharmacology Flashcards

1
Q

What is the main excitatory neurotransmitter of the CNS?

A

Glutamate

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2
Q

How much glutamate is required to kill neurons?

A

110mM within 5 minutes

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3
Q

Why do foods containing glutamate not cause neurotoxicity?

A

Glutamate does not cross the blood-brain barrier

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4
Q

What is glutamate produced from?

A
  1. The citric acid cycle from α-ketoglutarate using the enzyme glutamate dehydrogenase
  2. Transamination using another amino acid as the NH2 donor
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5
Q

How is extracellular glutamate removed from the synaptic cleft?

A

Sequestered into neighbouring glial cells and post-synaptic neurons by high affinity EAAT

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6
Q

What are the glial isoforms of EAAT?

A

EAAT 1 and 2

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7
Q

What are the neuronal isoforms of EAAT?

A

EAAT 3 and 4

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8
Q

Where is EAAT5 found?

A

The retina

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9
Q

How are EAATs powered?

A

Mainly by sodium gradient across cell membrane

Also membrane voltage and potassium gradient

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10
Q

What occurs to glutamate in glia?

A

Converted to glutamine by glutamine synthetase

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11
Q

How is glutamine converted to glutamate in the pre-synaptic nerve terminal?

A

Phosphate activated glutaminase

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12
Q

How is glutamate concentrated into synaptic vesicles?

A

By vesicular glutamate transporters

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13
Q

What are AMPA receptors?

A

Glutamate-gated mixed cation channels permeable mainly to Na+ and K+

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14
Q

How many subunits does each AMPA receptor have?

A

4 (it is a tetramer)

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15
Q

Where is the glutamate binding site situated on the AMPA receptor?

A

Between the N-terminal domain and the loop between TM3 and TM4

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16
Q

How does cocaine exposure affect the composition of AMPA receptors in the VTA?

A

Triggers expression of GluR2-lacking AMPA receptors that are permeable to calcium

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17
Q

What is the effect of mRNA editing in AMPA receptors?

A

Provides AMPA receptors with calcium impermeability

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18
Q

Where does mRNA editing in AMPA receptors occur?

A

Only in GluR2-containing receptors

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19
Q

How many glutamate molecules bind to one AMPA receptor?

A

4

One to each subunit

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20
Q

What is the result of continuous application of glutamate to AMPA receptors?

A

Rapid activation and subsequent rapid desensitisation

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21
Q

What causes AMPA desensitisation?

A

Rearrangement of receptor subunits

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22
Q

What is kainate?

A

AMPA agonist

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23
Q

Why is kainate highly neurotoxic?

A

Does not cause rapid desensitisation

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24
Q

What is domoic acid associated with?

A

Shellfish poisoning

25
Q

What does cyclothiazide do?

A

Blocks AMPA receptor desensitisation

Causes overexcitation

26
Q

What are the AMPA agonists?

A
  1. Glutamate
  2. Kainate
  3. Domoate
27
Q

What are the competitive AMPA agonists?

A
  1. NBQX

2. CNQX

28
Q

What is the effect of kainate receptor activation?

A

Either facilitate or inhibit at the presynaptic terminal

At low levels of activation, more likely to facilitate neurotransmitter release

At high levels of activation, more likely to inhibit neurotransmitter release

29
Q

How does NMDA receptor permeability differ from AMPA and kainate receptors?

A

More permeable to calcium ions

30
Q

What is required for NMDA receptor activation?

A

Glutamate binds to GluN2 subunit

Glycine binds to GluN1 subunit

31
Q

How does GluN2 modify the properties of the NMDA channel?

A

Changes zinc, pH and glycine sensitivity

32
Q

What is the effect of low extracellular pH on NMDA receptor activation?

A

Inhibits

Could be a safety factor for ischaemia

33
Q

Which receptor has the highest glutamate affinity?

A

NMDA

34
Q

What is the deactivation time of GluN2D?

A

4 seconds

35
Q

When is the NMDA receptor blocked?

A

Mg2+ blocks pore at negative membrane potentials

36
Q

When is the NMDA receptor unblocked?

A

When the membrane depolarises, it becomes more positive and repels the Mg2+ ion from the pore

37
Q

How much glutamate release is required for NMDA receptor activation?

A

Substantial release to sustain the membrane depolarisation enough to relieve the Mg2+ block, resulting in NMDA receptor activation and calcium influx

38
Q

What is the effect of phosphorylation of AMPA receptors?

A

Enhances their activity for an extended period

Long term potentiation

39
Q

What are the NMDA receptor antagonists?

A
  1. Memantine
  2. Ketamine

(open-channel blockers)

40
Q

What is a current clinical use of memantine?

A

Treatment of Alzheimer’s disease

41
Q

What is a current clinical use of ketamine?

A

Dissociative anaesthetic

Rapid antidepressant properties

42
Q

What type of drugs are NMDA agonists?

A

Convulsivant drugs

43
Q

What type of metabotropic receptors are group I mGluRs?

A

Gq/11

Usually post-synaptic

44
Q

What type of metabotropic receptors are group II/III mGluRs?

A

Gi/o

Usually mediate presynaptic inhibition

45
Q

What is mGluR6 responsible for?

A

Inhibitory action of glutamate at ON-bipolar cells in the retina

46
Q

What is the role of nitric oxide in neurons?

A

Retrograde messenger

Diffuses back to presynaptic neuron and enhances neurotransmitter release

47
Q

How do NMDA receptors mediate long term potentiation?

A
  1. Calcium enters post-synaptic neuron through NMDA receptor
  2. Binds to calmodulin-dependent protein kinase II
  3. Increased AMPA receptor expression in postsynaptic membrane
48
Q

How do NMDA receptors mediate long term depression?

A
  1. Calcium enters post-synaptic neuron through NMDA receptor
  2. Increases activity of calcineurin and protein phosphatase 1
  3. Causes internalisation of postsynaptic AMPA receptors and downregulation of NMDA receptors
49
Q

What is the difference between induction of LTP and LTD?

A

Magnitude and frequency of increases in calcium concentration

Frequent high increases recruit kinases

Low frequency, smaller increases recruit phosphatases

50
Q

What causes stroke?

A

Occlusion - 85%

Haemorrhage - 15%

51
Q

Which cells does stroke treatment aim to save?

A

Cells in the penumbra

There is very little that can be done for cells in the core

52
Q

What is the main first-line stroke treatment?

A

Rapid administration of clot-busting drugs

Must be done after CT scan to determine type of stroke

53
Q

How do strokes cause cell death?

A
  1. Na+/K+/ATPase pump does not have enough energy to function properly
  2. Electrolyte imbalance
  3. Membrane depolarised
    4a. Glu released opens NMDA channels, allowing Ca2+ in
    4b. Voltage-gated calcium channels activated allowing Ca2+ in
  4. Calcium causes cell death
54
Q

How does an increase in intracellular calcium cause cell death?

A
  1. Activates proteases and caspases that damage cellular architecture
  2. Peroxidises lipids
  3. Stimulates microglia to produce cytotoxic factors
  4. Disrupted mitochondrial function
  5. Induces pyknosis
55
Q

What are the other mechanisms of cell death in ischaemia?

A
  1. Zinc neurotoxicity - released by exocytosis
  2. Inflammation response
  3. Reperfusion injury
56
Q

Which drugs might be use to reduce cell death following stroke?

A
  1. Glutamate receptor antagonists
  2. Calcium channel blockers
  3. Sodium channel blockers
  4. GABA receptor agonists
57
Q

What is aptiganel?

A

Glutamate receptor antagonist

58
Q

What is nicardipine?

A

Calcium channel blocker

59
Q

What is lamotrigine?

A

Sodium channel blocker

NHB (17 decks)

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