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Mechanism of Drug Action > Neuropharmacology (Neurotransmission) > Flashcards

Neuropharmacology (Neurotransmission) Flashcards

1
Q

What is the fundamental property of all drugs that act on the CNS?

A

They all must cross the BBB

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2
Q

How do drugs cross the BBB?

A
  1. Drug is lipophilic/amphoteric
  2. Transporters present for drugs
  3. BBB becomes leaky due to pathology
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3
Q

What is volume transmission?

A

As opposed to fast transmission mediated by some neurotransmitters at closely opposed synapses, some NTs are released from varicosites and diffuse longer distance before acting on target post-synaptic receptors.

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4
Q

What is the role of glutamate in CNS?

A

Main excitatory NT

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5
Q

How is glutamate synthesised?

A
  1. α-ketoglutarate (TCA cycle) →(Glutamate dehydrogenase)→ Glutamate
  2. Transamination with another amino acid as -NH2 donor
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6
Q

How is Glu transported into vesicles?

A
  1. VGLUT1 & VGLUT2: Ubiquitous in all cells
  2. VGLUT3: Limited distribution
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7
Q

What are the effects of reduced VGLUT1 activity?

A
  1. Anxiety
  2. Depression
  3. Reduced long-term memory
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8
Q

What are the effects of reduced VGLUT2 activity?

A
  1. Reduced neuropathic pain
  2. Schizophrenia-like symptoms
  3. Reduced anxiety
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9
Q

How is Glu transmission terminated?

A

Transport into surrounding glial cells and post-synaptic neurone

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10
Q

What mediates Glu transport into cells?

A

Excitatory amino acid transporters (EAATs)

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11
Q

What are the types of EAATs?

A
  • EAAT-1,2 (glial cells)
  • EAAT-3,4 (post-synaptic neurones)
  • EAAT-5 (retina)
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12
Q

How can EAAT action be disrupted?

A
  1. Disrupting Na+ gradient
  2. Disrupting membrane potential
  3. Disrupting K+ gradient

All these factors contribute to providing energy for EAAT action

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13
Q

What is the Glutamate-glutamine cycle?

A
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14
Q

What are the types of Glu receptors?

A

Ionotropic:

  1. AMPA
  2. NMDA
  3. Kainate

Metabotrophic: mGluR

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15
Q

What is the structure of AMPA Glu receptors?

A
  • Tetramer
  • Each subunit has 4 TM domains
  • Glu binding site between N-terminus and TM3/TM4 loop region
  • TM2 makes up selectivity filter (?)
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16
Q

What needs to happen for AMPA Glu receptors to be activated?

A

Binding of Glu onto all 4 subunits

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17
Q

What is the ionic specificity of AMPA receptors?

A

Na+ & K+

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18
Q

How many different types of AMPA subunits are there?

A

4 (GluA1-4)

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19
Q

What are the event that occur following continuous stimulation of the AMPA receptors?

A
  1. Desensitisation due to rearrangement of subunits
  2. Deactivation due to removal from PM
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20
Q

What is the structure of Glu kainate receptors?

A
  • Tetramer
  • Pre-synaptic and post-synaptic
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21
Q

What is the ionic specificity of kainate receptors?

A

Ca2+

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22
Q

What are the functions of pre-synaptic kainate receptors?

A
  • High [Glu] → -ve feedback of Glu release
  • Low [Glu] → +ve feedback of Glu release
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23
Q

How many different types of kainate subunits are there?

A

5 (GluK1-5)

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24
Q

What is the structure of NMDA receptors?

A
  • Tetramer
  • Contains 2 GluN1 and 2 GluN2 receptors
  • Post-synaptic
25
What are the different types of NMDA subunits?
1. GluN1 2. GluN2(A-D)
26
What is the ionic selectivity of NMDA receptors?
Ca2+
27
What are the events that need to take place in order for NMDA receptor activation to occur?
1. Glu binds to GluN2 subunits 2. Co-agonist (glycine/D-serine) binds to GluN1 subunits 3. Depolarisation of PM (relief of Mg2+ block)
28
What are the relative Glu affinities of NMDA and AMPA receptors and why is this significant?
- AMPA has higher affinity compared to NMDA - NMDA needs to be directly opposite site of Glu vesicular release from pre-synaptic terminal to be activated because otherwise AMPA receptors bind to most Glu before it can bind to NMDA
29
What are the effects of NMDA receptor inhibition?
Schizophrenia-like symptoms
30
What are the types of mGluRs?
- Group I (mGluR 1,5): Gs-coupled (mainly post-synaptic effects) - Group II (mGluR 2,3): Gi/o-coupled (mainly pre-synaptic effects) - Group III (mGluR 4, 6-8): Gi/o-coupled (mainly pre-synpatic effects)
31
What are the pre-synaptic effects of mGluRs?
1. Opening K+ channels 2. Inhibtion of Ca2+ channels 3. Reduction of pre-synaptic [cAMP]
32
What are the post-synpatic effects of mGluRs?
1. Activation of NOS and synthesis of NO, which acts as retrograde messenger in pre-synaptic membrane to increase transmitter release 2. Activation of PKC causes phosphorylation of post-synpatic receptors and increases sensitivity
33
What are the NTs that mediate fast inhibitory neurotransmission in the CNS?
1. Glycine: Main inhibitory NT in spinal cord (and excitatory in brain) 2. GABA: Main inhibitory NT in brain
34
How is GABA synthesised?
Krebs cycle ↓ α-ketoglutarate ↓ (GABA-transaminase) ↓ Glutamate ↓ (Glutamic acid decarboxylase (GAD)) ↓ GABA
35
How is GABA metabolised?
GABA ↓ (GABA-transaminase) ↓ Succinic semialdehyde ↓ (Succinic semialdehyde dehydrogenase) ↓ Succinic acid ↓ Krebs cycle
36
What mediates GABA uptake into vesicles?
Vesicular inhibitory amino acid transporter (VIAAT), otherwise known as vesicular GABA transporter (VGAT)
37
How is GABA transmission terminated?
Uptake into pre-synpatic terminal or surrounding astrocytes by GABA transporter (GAT)
38
What are the different types of GABA receptors and their locations?
- GABAA - GABAB
39
What are the locations of GABA receptors?
Pre-synaptic and post-synaptic
40
What is the structure of the GABAA receptors?
- Pentameric - 20 different possible subunits - Each subunit has 4 TM domains - TM2 domain lines the pore - Most common combination is 2xα, 2xβ and 1xγ
41
What are the different ligand binding sites on GABAA receptors?
- GABA binding site lies on β subunits, but GABA also interacts with α - Benzodiadepine binding site on α but γ also required for binding
42
What is the structure of the GABAB receptor?
- Gi/o-coupled GPCR - Dimers held together by coil-coil interactions between C-terminus end
43
What are the locations of GABAB receptors?
Pre-synaptic and post-synaptic
44
What is the process of 5-HT synthesis?
Tryptophan ↓ (Tryptophan hydroxylase) ↓ 5-Hydroxytryptophan ↓ (Aromatic L-amino acid decarboxylase) ↓ 5-HT
45
Whatr is the rate-limiting step in 5-HT synthesis?
Tryptophan → 5-Hydroxytryptophan (due to availability of tryptophan)
46
How is 5-HT metabolised?
MAO
47
What are the roles of 5-HT in central transmission?
1. Mood 2. Sleep/wakefulness 3. Appetite/feeding 4. Behaviour/hallucinations 5. Sensory transduction
48
What is atypical about 5-HT3 receptors?
They are neuromodulatory ion channels
49
How is dopamine synthesised?
Tyrosine ↓ (Tyrosine hydroxylase) ↓ DOPA ↓ (DOPA decarboxylase) ↓ Dopamine
50
How is dopamine metabolised?
- MAO and COMT - Metabolised to to DOPAC and HVA
51
How is dopamine transported into vesicles?
VMAT
52
How is dopamine removed from synapses?
Dopamine transporter (DAT)
53
What is the function of dopamine in the brain?
1. Movement control - Nigrostriatal pathway 2. Executive functions & reward - Mesolimbic/mesocortical pathway 3. Regulation of hormone secretion - Tubero-infundibular system
54
What are the types of dopamine receptors?
- D1 - D5 - D1-like (D1, D5) - D2-like (D2-D4)
55
What are the locations of dopamine receptors?
- Mostly widely distributed - Pituitary expresses mostly D2 - Reduced expression of D3 in striatum
56
What conditions can be treated by modulating dopamine pathway?
- ADHD - Parkinson's disease 3. Schizophrenia
57
What are the roles of different mAChRs in the CNS?
M1, 3,4 - Cortex and hippocampus (learning & memory) M1, 4 - Extrapyramidal motor circuits
58
How is histamine synthesised?
Histidine ↓ (L-amino acid decarboxylase - LAAD) ↓ Histamine
59
How is histamine metabolised?
1. MAO 2. Diamine oxidase 3. Histamine methyltransferase

Mechanism of Drug Action (28 decks)

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