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GABA Flashcards

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1
Q

Why is GABA important?

A

main inhibitory neurotransmitter in the CNS (10-40% of
neurons in cortex, hippocampus, and substantia nigra)

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2
Q

What is its cellular function?

A
  • Increases the conductance of chloride ions across cell
    membranes
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3
Q

What NT is similar to it?

A

Glycine

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4
Q

What enzyme converts glutamate to GABA?

A

GAD = Glutamatic acid decarboxylase

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5
Q

What is the name of the GABA transporter?

A

Vesicular GABA transporter
(VGAT)

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6
Q

What NTs does it work with?

A

GABA and glycine

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7
Q

What is VGAT’s function?

A

VGAT identifies both
GABAergic and glycinergic
neurons in the CNS

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8
Q

What do GABA inhibitors do?

A

Cause convulsive activity

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9
Q

What are the experimental GAD antagonists?

A
  • allylglycine
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10
Q

Describe the effects of GAD inhibition

A

decreases GABA levels and leads to
convulsive activity

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11
Q

Where is GAT-1 found?

A

on neurons and
astrocytes

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12
Q

Where is GAT-2 and 3 found?

A

Principally astrocytic.

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13
Q

Describe tiagabine

A

A selective antagonist of GAT-1 and elevates GABA levels in the synapse.

  • Approved as an adjunctive AED for epilepsy
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14
Q

Describe vigabatrin

A

Irreversible inhibitor of GABA-T and elevates GABA levels in the brain by blocking breakdown

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15
Q

Where is GABA generally found?

A

widely used in inhibitory interneurons throughout the brain

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16
Q

Describe chandelier cells

A

Chandelier cells of the cortex synapse onto the axonal initial segment of pyramidal cells

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17
Q

Describe basket cells

A

Basket cells of the cerebellum, hippocampus, and cortex form axo-somatic synapses onto target
cells

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18
Q

What are the 2 types of GABAergic synapses?

A

Axo-axonal and axo-somatic

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19
Q

What are Purkinje cells?

A

large GABAergic projection neurons of the cerebellum

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20
Q

What are the functions of Purkinje cells?

A

Provide the sole output of motor coordination from the
cerebellar cortex

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21
Q

What controls Purkinje cells?

A

GABAergic
interneurons

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22
Q

What is Holmes
cerebellar degeneration?

A

Degeneration of Purkinje neurons

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23
Q

What are the symptoms of Holmes
cerebellar degeneration?

A

Impaired fine hand movement, speech deficits, tremors, and ataxia while walking

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24
Q

Describe GABAergic control of motor initiation

A
  • Medium spiny neurons comprise 90-95% of the neurons in the
    striatum
  • Inputs from neocortex (all except visual and auditory)
  • Outputs to globus pallidus and substantia nigra
  • Involved in two pathways that control initiation of motor activity in the basal ganglia
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25
Q

Describe the direct pathway

A

Excitatory input (glutamatergic): cortex –>
medium spiny neurons (MSN) in striatum.

Inhibitory output: medium spiny neurons –> internal globus pallidus & substantia nigra pars reticula
(SNpr).

GABAergic MSN inhibit tonic inhibitory output from globus pallidus → ventral thalamus (VTh) and from SNpr → superior colliculus.

Disinhibits outputs:
VTh– excitatory projections to upper motor neurons of cortex
Superior colliculus– controlling eye saccades

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26
Q

Describe the indirect pathway

A

Medium spiny neurons project to the external
globus pallidus which forms a loop with the
subthalamic nuclei.

Subthalamic nuclei (STN) has excitatory
glutamatergic projections to the internal
globus pallidus.
Indirect pathway activation leads to
disinhibition of STN projections and thus
inhibition of motor output (dis-disinhibitory
pathway).

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27
Q

Describe the role of dopamine

A

Dopamine plays a gating role and balances activity between the direct and indirect pathways.

28
Q

Why is the D1 pathway promoted over D2?

A

Activation of nigrostriatal dopamine
pathways

29
Q

What happens in Parkinson’s?

A

In Parkinson’s the loss of dopaminergic
projections shifts activity to the indirect pathway.

30
Q

Describe cholinergic interneurons

A

Cholinergic interneurons in the
striatum receive excitatory inputs from
the cortex.

31
Q

Where do they act?

A

directly
on the direct pathway.

32
Q

Describe early interventions in Parkinson’s

A

M4AChR antagonists and AChE
inhibitors are useful therapeutics in
early Parkinson’s as they compensate
for decreased dopaminergic input.

33
Q

Describe GABAA receptors

A
  • Ionotropic

Classic ligand gated ion channel permeable to Cl-
5 subunits form the channel pore
Originally characterized by sensitivity to bicucculine (comp. antagonist)

34
Q

Describe GABAB receptors

A
  • Metabotropic

G-protein coupled receptors
Gi– inhibits adenylate cyclase (↓ cAMP)
* Gβγ– opens G-protein coupled K+ channel (GIRK)
Originally characterized by sensitivity to baclofen (specific agonist)

35
Q

What are the 4 GABAA receptor binding sites?

A

GABA, Benzodiazepines, Barbituates and Neurosteroids

36
Q

What does the GABA binding site do?

A

binds two molecules of GABA at
the interface between α and β subunits

37
Q

What does the benzodiazepine site do?

A

binds benzodiazepines
(tranquilizers) as positive allosteric modulators

38
Q

What does the barbiturate site do?

A

binds barbiturates (sedative &
anxiolytics) as positive allosteric modulators

39
Q

What does the neurosteroid site do?

A

binds endogenous
neurosteroids as positive or negative allosteric
modulators

40
Q

What is picrotoxin?

A

a non-competitive channel blocker

41
Q

Describe Pentylenetetrazol

A
  • binds in the pore at the same site as picrotoxin and
    was used as a convulsant for depression therapy
  • Discontinued due to high risks of spontaneous seizure
  • Widely replaced with electroconvulsive therapy in 1939
42
Q

What is the competitive antagonist of the GABA binding site?

A

bicucculine– potent convulsant

  • Widely used in animal models of epilepsy
43
Q

What is the the agonist of the GABAsite?

A

muscimol

44
Q

What is fly agaric the source of?

A

muscarinic AChR agonist muscarine

GABAA agonist muscimol

45
Q

What are the characteristics of fly agaric?

A
  • Potent hallucinogen
  • Induces macroscopia
  • Perception of objects being larger than they are
46
Q

What are the effects of fly agaric?

A
  • Consumption of fly agaric has serious peripheral
    side-effects due to muscarinic cholinergic effects at
    NMJ and parasympathomimetic effects
47
Q

What is Gaboxidol?

A

a synthetic version of muscimol with
reduced psychotropic effects

48
Q

What are the characteristics of Gaboxidol?

A
  • Anxiolytic and analgesic
  • Potential insomnia treatment
49
Q

Describe benzos

A
  • Sedative-hypnotic, anxiolytic
  • Diazepam (Valium) one of the best known
  • Better safety margin than barbiturates
  • Binding causes increased probability of pore
    opening
  • High risks of drug interactions at the GABAA
    receptor
  • Orphan receptor site:
  • Endogenous ligand not known
  • Proposed ligands include inosine, peptides
    such as diazepam binding inhibitor/acyl-CoA
    binding protein, and small molecules called
    endozepines
50
Q

Describe barbiturates

A
  • Sedative-hypnotic, anaesthetic
  • Phenobarbitol best known
  • Narrow safety margin
  • High potential for abuse
  • High risk of overdose
  • Binding prolongs open time of Cl- pore
  • Used in physician-assisted suicide and euthanasia
  • Sodium amytal (amobarbital) is a barbiturate
    known as a ‘truth serum’
  • Helps to circumvent inhibitions
51
Q

What is ethanol?

A

potent positive allosteric modulator of GABAA binding
to a site on the transmembrane surface of the δ-subunit

52
Q

What alcoholic
effects is GABA connected to?

A

it’s sedative, euphoric, and addictive effects
through modulation of GABAA

53
Q

Describe GABAA’s affinity to ethanol

A
  • Ethanol binds GABAA with very high affinity – binding even at doses that would be considered moderate, social levels
54
Q

What is propofol?

A
  • Propofol is a potent anaesthetic that interacts with the
    transmembrane surface of the β-subunit of GABAA
  • Positive allosteric modulator that increases channel open time
55
Q

Briefly describe GABAB receptors

A
  • Primarily affect excitability by coupling to GIRK
  • GIRK activation is inhibitory by allowing K+ efflux which hyperpolarizes the cell
  • GABAA is responsible for fast, weak inhibitory postsynaptic potential (IPSP) signalling
  • Reversal potential Cl- ~ -70 mV
  • GIRK is responsible for slow, strong component of IPSP
  • Reversal potential K+ ~ -90 mV
  • Baclofen is a specific agonist of GABAB and is a muscle relaxant and antispastic
56
Q

Describe GHB

A

a weak GABAB agonist

  • Excitatory at the GHB receptor at lower doses → recreational drug use
    • euphoria, disinhibition, empathogenic
  • Inhibitory at GABAB at higher doses → ‘date rape drug’
  • Sedation, nausea, dizziness, and unrouseable sleep
57
Q

Describe GIRK

A
  • K+ channel activated during GPCR signalling
  • GIRK opens on binding of Gβγ (the otherwise regulatory component of the G-protein complex)
  • K+ exits the cell causing hyperpolarization of the cell membrane
  • GIRK signalling inhibits subsequent depolarizing stimuli
58
Q

Describe GABAA rho receptor

A
  • Insensitive to baclofen and
    bicucculine– lacks binding sites for
    benzodiazepines, barbiturates, and
    neurosteroids
  • More sensitive to GABA (having 5
    GABA binding sites)
  • Found in bipolar cells of the retina
  • Receive inhibitory signals from amacrine
    and horizontal cells
  • Mutations in GABAA-ρ are associated
    with heritable cases of retinitis
    Pigmentosa
59
Q

Describe GABA development

A

late developmental
step and is associated with maturation of impulse control, working
memory, and executive function

60
Q

Describe anxiety disorders

A
  • E.g. Generalized anxiety disorder, social anxiety disorder, panic disorder, post-
    traumatic stress disorder
61
Q

What are the effects of GABA agonists and positive allosteric modulators on anxiety disorders?

A

Anxiolytic

62
Q

Describe first anxiety and GABA model

A

Anxiety is caused by secretion of endogenous inverse agonists of GABAR →
inhibition of GABAR increases anxiety?

63
Q

Describe second anxiety and GABA model

A

Ligand activity at GABAR is shifted in anxiety (subunit alterations?)

64
Q

Describe third anxiety and GABA model

A

Secretion of endogenous agonists of benzodiazepine site during stressful
conditions → deficit in anxiety disorders?

65
Q

Describe role of GABA in development

A
  • High levels of GABA and developmental changes in GABA
    activity (excitatory / inhibitory switch)
  • GABA may contribute to cell proliferation, survival, and motility
  • Excitatory / Inhibitory balance is important in normal brain
    development
  • E/I balance is affected in conditions such as Down’s syndrome and Autism
66
Q

Describe link between GABA and epilepsy

A
  • Excitatory / Inhbitory balance implicated in seizure disorders
  • Drugs that decrease GABA levels or inhibit GABAR function are
    convulsant
  • Drugs that increase GABA levels or increase GABAR function are
    anticonvulsant
  • E/I imbalance in Down’s syndrome and Autism correlate with
    increased risk of seizure disorders
67
Q

Describe GABA and psychiatric disorders

A
  • GABA has been implicated or suggested to play a role in numerous neuropsychiatric & neurodegenerative disorders
  • Developmental disorders (ASD)
  • Addiction
  • Learning disorders
  • Schizophrenia
  • Tardive dyskinesia
  • Huntington’s disease
  • Parkinson’s disease
  • Generally proposed to contribute to hyperactivity through decreased
    inhibitory signalling

Psych 478 (28 decks)

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