CNS Pharmacology

Question 1

What is the main excitatory neurotransmitter of the CNS?

Answer 1

Glutamate

Question 2

How much glutamate is required to kill neurons?

Answer 2

110mM within 5 minutes

Question 3

Why do foods containing glutamate not cause neurotoxicity?

Answer 3

Glutamate does not cross the blood-brain barrier

Question 4

What is glutamate produced from?

Answer 4

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

Question 5

How is extracellular glutamate removed from the synaptic cleft?

Answer 5

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

Question 6

What are the glial isoforms of EAAT?

Answer 6

EAAT 1 and 2

Question 7

What are the neuronal isoforms of EAAT?

Answer 7

EAAT 3 and 4

Question 8

Where is EAAT5 found?

Answer 8

The retina

Question 9

How are EAATs powered?

Answer 9

Mainly by sodium gradient across cell membrane

Also membrane voltage and potassium gradient

Question 10

What occurs to glutamate in glia?

Answer 10

Converted to glutamine by glutamine synthetase

Question 11

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

Answer 11

Phosphate activated glutaminase

Question 12

How is glutamate concentrated into synaptic vesicles?

Answer 12

By vesicular glutamate transporters

Question 13

What are AMPA receptors?

Answer 13

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

Question 14

How many subunits does each AMPA receptor have?

Answer 14

4 (it is a tetramer)

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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

Question 17

What is the effect of mRNA editing in AMPA receptors?

Answer 17

Provides AMPA receptors with calcium impermeability

Question 18

Where does mRNA editing in AMPA receptors occur?

Answer 18

Only in GluR2-containing receptors

Question 19

How many glutamate molecules bind to one AMPA receptor?

Answer 19

4

One to each subunit

Question 20

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

Answer 20

Rapid activation and subsequent rapid desensitisation

Question 21

What causes AMPA desensitisation?

Answer 21

Rearrangement of receptor subunits

Question 22

What is kainate?

Answer 22

AMPA agonist

Question 23

Why is kainate highly neurotoxic?

Answer 23

Does not cause rapid desensitisation

Question 24

What is domoic acid associated with?

Answer 24

Shellfish poisoning

Question 25

What does cyclothiazide do?

Answer 25

Blocks AMPA receptor desensitisation Causes overexcitation

Question 26

What are the AMPA agonists?

Answer 26

1. Glutamate 2. Kainate 3. Domoate

Question 27

What are the competitive AMPA agonists?

Answer 27

1. NBQX | 2. CNQX

Question 28

What is the effect of kainate receptor activation?

Answer 28

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

Question 29

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

Answer 29

More permeable to calcium ions

Question 30

What is required for NMDA receptor activation?

Answer 30

Glutamate binds to GluN2 subunit Glycine binds to GluN1 subunit

Question 31

How does GluN2 modify the properties of the NMDA channel?

Answer 31

Changes zinc, pH and glycine sensitivity

Question 32

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

Answer 32

Inhibits Could be a safety factor for ischaemia

Question 33

Which receptor has the highest glutamate affinity?

Answer 33

NMDA

Question 34

What is the deactivation time of GluN2D?

Answer 34

4 seconds

Question 35

When is the NMDA receptor blocked?

Answer 35

Mg2+ blocks pore at negative membrane potentials

Question 36

When is the NMDA receptor unblocked?

Answer 36

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

Question 37

How much glutamate release is required for NMDA receptor activation?

Answer 37

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

Question 38

What is the effect of phosphorylation of AMPA receptors?

Answer 38

Enhances their activity for an extended period Long term potentiation

Question 39

What are the NMDA receptor antagonists?

Answer 39

1. Memantine 2. Ketamine (open-channel blockers)

Question 40

What is a current clinical use of memantine?

Answer 40

Treatment of Alzheimer's disease

Question 41

What is a current clinical use of ketamine?

Answer 41

Dissociative anaesthetic Rapid antidepressant properties

Question 42

What type of drugs are NMDA agonists?

Answer 42

Convulsivant drugs

Question 43

What type of metabotropic receptors are group I mGluRs?

Answer 43

Gq/11 Usually post-synaptic

Question 44

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

Answer 44

Gi/o Usually mediate presynaptic inhibition

Question 45

What is mGluR6 responsible for?

Answer 45

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

Question 46

What is the role of nitric oxide in neurons?

Answer 46

Retrograde messenger Diffuses back to presynaptic neuron and enhances neurotransmitter release

Question 47

How do NMDA receptors mediate long term potentiation?

Answer 47

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

Question 48

How do NMDA receptors mediate long term depression?

Answer 48

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

Question 49

What is the difference between induction of LTP and LTD?

Answer 49

Magnitude and frequency of increases in calcium concentration Frequent high increases recruit kinases Low frequency, smaller increases recruit phosphatases

Question 50

What causes stroke?

Answer 50

Occlusion - 85% | Haemorrhage - 15%

Question 51

Which cells does stroke treatment aim to save?

Answer 51

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

Question 52

What is the main first-line stroke treatment?

Answer 52

Rapid administration of clot-busting drugs Must be done after CT scan to determine type of stroke

Question 53

How do strokes cause cell death?

Answer 53

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 5. Calcium causes cell death

Question 54

How does an increase in intracellular calcium cause cell death?

Answer 54

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

Question 55

What are the other mechanisms of cell death in ischaemia?

Answer 55

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

Question 56

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

Answer 56

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

Question 57

What is aptiganel?

Answer 57

Glutamate receptor antagonist

Question 58

What is nicardipine?

Answer 58

Calcium channel blocker

Question 59

What is lamotrigine?

Answer 59

Sodium channel blocker