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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
Q

What are the different types of NMDA subunits?

A
  1. GluN1
  2. GluN2(A-D)
26
Q

What is the ionic selectivity of NMDA receptors?

A

Ca2+

27
Q

What are the events that need to take place in order for NMDA receptor activation to occur?

A
  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
Q

What are the relative Glu affinities of NMDA and AMPA receptors and why is this significant?

A
  • 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
Q

What are the effects of NMDA receptor inhibition?

A

Schizophrenia-like symptoms

30
Q

What are the types of mGluRs?

A
  • 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
Q

What are the pre-synaptic effects of mGluRs?

A
  1. Opening K+ channels
  2. Inhibtion of Ca2+ channels
  3. Reduction of pre-synaptic [cAMP]
32
Q

What are the post-synpatic effects of mGluRs?

A
  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
Q

What are the NTs that mediate fast inhibitory neurotransmission in the CNS?

A
  1. Glycine: Main inhibitory NT in spinal cord (and excitatory in brain)
  2. GABA: Main inhibitory NT in brain
34
Q

How is GABA synthesised?

A

Krebs cycle

↓

α-ketoglutarate

↓
(GABA-transaminase)
↓

Glutamate

↓
(Glutamic acid decarboxylase (GAD))
↓

GABA

35
Q

How is GABA metabolised?

A

GABA

↓
(GABA-transaminase)
↓

Succinic semialdehyde

↓
(Succinic semialdehyde dehydrogenase)
↓

Succinic acid

↓

Krebs cycle

36
Q

What mediates GABA uptake into vesicles?

A

Vesicular inhibitory amino acid transporter (VIAAT), otherwise known as vesicular GABA transporter (VGAT)

37
Q

How is GABA transmission terminated?

A

Uptake into pre-synpatic terminal or surrounding astrocytes by GABA transporter (GAT)

38
Q

What are the different types of GABA receptors and their locations?

A
  • GABAA
  • GABAB
39
Q

What are the locations of GABA receptors?

A

Pre-synaptic and post-synaptic

40
Q

What is the structure of the GABAA receptors?

A
  • 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
Q

What are the different ligand binding sites on GABAA receptors?

A
  • 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
Q

What is the structure of the GABAB receptor?

A
  • Gi/o-coupled GPCR
  • Dimers held together by coil-coil interactions between C-terminus end
43
Q

What are the locations of GABAB receptors?

A

Pre-synaptic and post-synaptic

44
Q

What is the process of 5-HT synthesis?

A

Tryptophan

↓
(Tryptophan hydroxylase)
↓

5-Hydroxytryptophan

↓
(Aromatic L-amino acid decarboxylase)
↓

5-HT

45
Q

Whatr is the rate-limiting step in 5-HT synthesis?

A

Tryptophan → 5-Hydroxytryptophan (due to availability of tryptophan)

46
Q

How is 5-HT metabolised?

A

MAO

47
Q

What are the roles of 5-HT in central transmission?

A
  1. Mood
  2. Sleep/wakefulness
  3. Appetite/feeding
  4. Behaviour/hallucinations
  5. Sensory transduction
48
Q

What is atypical about 5-HT3 receptors?

A

They are neuromodulatory ion channels

49
Q

How is dopamine synthesised?

A

Tyrosine

↓
(Tyrosine hydroxylase)
↓

DOPA

↓
(DOPA decarboxylase)
↓

Dopamine

50
Q

How is dopamine metabolised?

A
  • MAO and COMT
  • Metabolised to to DOPAC and HVA
51
Q

How is dopamine transported into vesicles?

A

VMAT

52
Q

How is dopamine removed from synapses?

A

Dopamine transporter (DAT)

53
Q

What is the function of dopamine in the brain?

A
  1. Movement control - Nigrostriatal pathway
  2. Executive functions & reward - Mesolimbic/mesocortical pathway
  3. Regulation of hormone secretion - Tubero-infundibular system
54
Q

What are the types of dopamine receptors?

A
  • D1 - D5
  • D1-like (D1, D5)
  • D2-like (D2-D4)
55
Q

What are the locations of dopamine receptors?

A
  • Mostly widely distributed
  • Pituitary expresses mostly D2
  • Reduced expression of D3 in striatum
56
Q

What conditions can be treated by modulating dopamine pathway?

A
  • ADHD
  • Parkinson’s disease
    3. Schizophrenia
57
Q

What are the roles of different mAChRs in the CNS?

A

M1, 3,4 - Cortex and hippocampus (learning & memory)

M1, 4 - Extrapyramidal motor circuits

58
Q

How is histamine synthesised?

A

Histidine

↓
(L-amino acid decarboxylase - LAAD)
↓

Histamine

59
Q

How is histamine metabolised?

A
  1. MAO
  2. Diamine oxidase
  3. Histamine methyltransferase

Mechanism of Drug Action (28 decks)

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