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BS32024 > GABA and Benzodiazepines > Flashcards

GABA and Benzodiazepines Flashcards

1
Q

What does GABA stand for?

A

Gamma-aminobutyric acic

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2
Q

How is GABA made?

A

GABA is an amino acid neurotransmitter
Made from glutamate by the enzyme glutamic acid decarboxylase

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2
Q

What is the main function of GABA?

A

Inhibitory
Makes the neuron less likely to fire an AP or release neurotransmitters

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3
Q

GABA Receptors

A

2 types:
GABAA and GABAB

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4
Q

GABAA Receptors

A

Ionotropic
Opens chlorine channel > chlorine enters neuron > hyperpolarises neuron

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5
Q

GABAB Receptors

A

Metabotropic/GPCR
Activation of receptor opens different potassium receptor > potassium leaves neuron > neuron hyperpolarises

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6
Q

Termination of GABA

A

GABA transporters take up GABA from the synapse into the neuron or glial cells, where GABA is degraded primarily by mitochondrial enzymes

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7
Q

Sedative effects of GABA

A

Increased GABA activity = reduced neural transmission = sedative effects
Alcohol and benzidiazepines (ie diazepam) increase activity at the GABA receptor

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8
Q

What are the (side)effects of drugs enhacing GABAaR function?

A

Effects:
Anxiolytic (reduces anxiety)
Anticonvulsant
Analgesic (reduces pain)
Amnestic (loss of memory)
Sedative/Hypnotic
Anaesthetic

Side effects:
Impair cognition
Produce tolerance
Become addictive

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9
Q

What drugs enhance GABAaR function?

A

Benzodiazepines, steroids, barbiturates

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10
Q

What are PAMs of the GABAaR? Give examples

A

PAMs are Positive Allosteric Modulators (enhance function)
Bind at the benzodiazepine binding site
Bind between the alpha and gamma subunit interface

Examples: diazepam, flunitrazepam

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11
Q

What are NAMs of the GABAaR? Give examples

A

NAMs are Negative Allosteric Modulators (decrease function)
Bind at benzodiazepine binding site
Bind between the alpha and gamma subunit interface

Examples: DMCM (a beta-carboline that is pro-convulsant and anxiogenic)

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12
Q

What are antagonists of the GABAaR? Give examples

A

Antagonists do not influence the action of GABAaR but prevent the action of PAMs and NAMs
Bind between the alpha and gamma subunit interface

Example: flumazenil (inert)

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13
Q

What are the most commone GABAaR subtypes?

A

alpha1,beta-gamma2 > alpha3, beta-gamma2 > alpha2, beta-gamma2

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14
Q

GABAaR with apla1-beta1-gamma2 subunits

A

Benzodiazepine sensitive
Benzodiazepines bind between the alpha and gamma subunit interface
Benzodiazepine only enhances GABA responses for the alpha1-beta1 subunits joined with gamma2 (for other gammas it does not)

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15
Q

What does diazepam need to facilitate (high affinity) binding?

A

For high affinity bidning, the binding site must contain a gamme subunit, usually gamma2

Gamma2 + alpha1,2,3, or 5 are diazepam sensitive (have H residue at position 101)

Gamma2 + alpha6 or 4 are diazepam insensitive (have R residue at position 101)

16
Q

alpha1H101R mouse

A

Causes loss of 3H-flumazenil binding binding in areas known to express alpha1
Sedative (not myorelaxant) effects of diazepam are blunted (not blunted in alpha2H101R mouse)
Anxiolytic, not sedative

17
Q

alpha2H101R mouse

A

alpha2-beta-gamma2 GABAaRs mediate the anxiolytic effects of diazepam
Can be tested with the light/dark box, or elevated plus maze
Anxiolytic effects do not occur in alpha2H101R
Sedative, not anxiolytic

18
Q

Function of benzodiazepines in inflammatory and neuropathic pain? What are the testing methods?

A

Intrathecal (injected into the spinal cord) diazepam supresses response to heat and mechanical stimuli
Primarily mediated by alpha2/3 GABAaRs
These effects are maintained in the alpha1H101R mouse but not the alpha2H101R mouse

Heat hyperalgesia - paw withdrawal latency upon exposure to defined radiant heat

Mechanical sensitisation - paw withdrawal with Von-Frey filaments

Cold allodynia (pain from harmless stimulation) - time spent lifting, shaking, licking paw after drop of acetone

19
Q

alpha5-NAMs as cognitive enhancers?

A

Diazepam/flunitrazepam impair cognition (esp. + alcohol)

NAMs of alpha5-beta-gamma2 subtype exhibit pro-cognitive properties in mouse models of:
HD
Alzheimer’s
Down’s syndrome

Also enhances impaired hippocampal CA1 long term potentiation (LTP)

20
Q

How is cognition assessed in mice?

A

Morris water maze
Novel object recognition task

21
Q

Relation between alpha5-GABAaRs and cognition?

A

Expressed extrasynaptically in hippocampal CA1 neurons (mediate tonic current)

alpha5 knockout mouse shows improved performance in water maze

Cognitive impairment associated with diazepam is absent in alpha5 knockout mice

NAMs of alpha5 GABAaRs improve cognition and LTP in mouse models of HD, alzheimer’s and Down syndrome

22
Q

Overview of the function of benzodiazepines on different alpha subunit GABAaRs

A

Alpha1 - sedative
Alpha 2 - anxiolytic, analgesic
Alpha5 - impairs cognition

23
Q

How are novel GABAaR subtype-selective benzodiazepines identified?

A
  1. Compound synthesis
  2. Displacement of 3H-flunitrazepam from rat brain membranes (determines affinity for receptor)
  3. Displacement of 3H-flunitrazepam from cell lines expressing recombinant human GABAaRs (affinity for human receptor and various subtypes)
  4. Functional electrophysiological studies with a) cell lines expressing recombinant GABAaRs and b) neuronal GABAaRs (determines appropriate efficacy)
  5. Appropriate pharmokinetics:
    CNS receptor occupancy
    Changes in EEG activity (mouse/rat) (determines whether it can cross the blood/brain barrier, and the duration of action)
  6. Behavioural studies:
    Sedation/self-administration - alpha1
    Anxiolytic/analgesic - alpha2/3
    Cognition - alpha5
    (behavioural profile)
24
Q

What is the IC50?

A

Concentration of a drug required to displace 50% of the specific binding of the ligand

25
Q

What does an assay of GABAaRs expressed in cell lines look like?

A

Transfect cells with GABAaR subunit cDNA and cDNA for GFP
1-2 days later record GABAaR mediated currents from green cells using whole cell clamps
-> effective concentration range and efficacy

Harvest cells, make a membrane homogenate and determine the displacement of the specific binding of 3H-flunitrazepam
-> binding affinity, not efficacy

26
Q

Fordetermining what is medium throughput electrophysiology a requirement?

A

Efficacy of chemical modifications of the active drug

Efficacy of large chemical libraries of compounds

27
Q

What is the difference between phasic and tonic inhibition?

A

Phasic - receptors responding to the ligand are located intrasynaptically

Tonic - receptors responding to the ligand are located extrasynaptically

BS32024 (5 decks)

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