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Neuropharmacology > Chapter 8: Glutamate And GABA > Flashcards

Chapter 8: Glutamate And GABA Flashcards

1
Q

Glutamine—>

A

Glutamate

Enzymes: glutaminase

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2
Q

Glutamine storage and release

A

VGLUT (vesicular glutamate transporter)- found only in cells that use Glu as NT

Either VGLUT1 or 2 are found in most neurons

      - VGLUT1- cortex and hippocampus
      - VGLUT2- subcortical structures

VGLUT3- inner hair cells of ear

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3
Q

Glutamate inactivation

A

Excitatory amino acid transporters (EAATs)

EAAT1/2- expressed by astrocytes
- astrocytes play most important role in taking up Glu after release

EAAT3- found on postsynaptic cells

EAAT4- Purkinje cells in cerebellum

EAAT5- bipolar cells of retina

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4
Q

Glutamate—>

A

Glutamine

Enzyme: glutamine synthetase
Location: astrocyte

*helps in metabolism and removal of ammonia

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5
Q

Glutamate is most abundant […] NT in the brain

A

Glutamate is most abundant excitatory NT in the brain

  • found in all neurons and glial cells
  • glutametergic neurons segregate Glu they use for transmission vs metabolism

Location:

  • Cortex
    - Pyramidal neurons- project to striatum, thalamus, limbic system structures, and brain stem
  • Cerebellum
    - Parallel fiber (GC’s) input to Purkinje neurons
  • Hippocampus
    - DG, CA1, CA3
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6
Q

The functional roles of Glu are important in neurotransmission, plasticity, and disease

A 
Fast excitatory neurotransmission
Learning and memory
      - neuronal plasticity
Neurological disorders
      - neurodegenerative disorders
      - cells death (excitotoxicity; apoptosis)

Possible involvement of Glu in drug addiction, schizophrenia, and other psychopathology

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7
Q

Glu is an agonist of both […] and […] receptors

A

Glu is an agonist of both ionotropic and metabotropic receptors

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8
Q

iGlu receptors

A

NMDA- Na+ and Ca2+ flow through channel
- Ca2+ activates 2nd- messenger system

non-NMDA- Na+ and K+ flows through receptor channels

   - AMPA
   - kainic acid (KA) - locomotor activity, coordination, and brain excitability
  • excitatory response
  • only has 4 subunits
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9
Q

mGlu receptors

A

Group I (mGlu1,5)- postsynaptic and excitatory responses via PIP2 system

Group II (mGlu2,3)- inhibit cAMP formation

Group III (mGlu4, 6 and 7)- inhibit cAMP formation
       - L-AP4 is selective agonist
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10
Q

Non-NMDA Pharmacology

A

Agonists: AMPA and kainic acid
Antagonist: NBQX

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11
Q

Non-NMDA Structure

A

GluA1-A4; GluA5-A7; KA1, KA2

4 subunits; dimer of dimers

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12
Q

Non-NMDA Physiology

A

Most AMPA/KA-R’s increases gNa+/gK+

GluA2- lacking AMPA receptors are Ca2+ permeable

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13
Q

NMDA receptors are highly regulated

A

Ligand and voltage gated
Subunits:
GluN1 x2: Ser and Gly bind
GluN2 x2: Glu binds

Channels only open if:

  1. Glu is released into NMDA receptors
  2. Cell membrane is depolarized by stimulation of different excitatory receptor
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14
Q

NMDA Co-agonists

A
  • Glutamate (NMDA)

- Glycine (D-serine)

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15
Q

NMDA receptor antagonists

A
  • Competitive: AP5 (APV)

- Non-competitive: PCP, MK-801, and Namenda, ketamine

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16
Q

NMDA Mg2+ block

A

Depolarization removes Mg2+ block

Highly Ca2+ permeable

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17
Q

Voltage-dependence of NR is due to […] in the […]

A

Voltage-dependence of NR is due to Mg2+ in the pore of the channel

Hyperpolarized Vm

    - Mg2+ blocks the channel
    - Non-conductive

Depolarized Vm

     - Mg2+ is expelled
     - Highly permeable to Ca2+
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18
Q

NMDA receptors are critical in some forms of […]

A

NMDA receptors are critical in some forms of LTP

  • Induction phase
  • Expression phase
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19
Q

Induction Phase of LTP

A
  • Depolarization
  • NMDA receptor activation
  • Ca2+ influx- activates protein kinases, including CAMKII
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20
Q

Expression phase of LTP

A

Many kinases phosphorylate several targets involved in AMPA receptor trafficking

  • Receptor trafficking- NT receptors continuously moved into and out of cell membrane
  • CAMKII can stay activated even after Ca2+ return to baseline
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21
Q

[…] enhance cognitive function

A

AMPA receptor modulators enhance cognitive function

  • Nootropics
  • Ampakines
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22
Q

Ampakines

A
  • Positive allosteric modulators of AMPA receptors
  • Prevent deactivation and/or desensitization
  • Increase channel open time
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23
Q

The ampakine […] improves performance on the delayed match-to-sample task

A

The ampakine CX717 improves performance on the delayed match-to-sample task

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24
Q

The ampakine […] increases dendritic arborization and spine density in aged rats

A

The ampakine CX929 increases dendritic arborization and spine density in aged rats

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25
Q

Excitotoxicity hypothesis

A

Prolonged neuronal depolarization leads to neuronal damage and/ or cell death

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26
Q

Three forms of cell death from strong activation of NMDA receptors

A

Necrosis- mode of cell death characterized by lysis of cell due to osmotic swelling

Apoptosis (programmed cell death)- disruption of nucleus, DNA breakup, and cell death (cleared out by phagocytosis)

Programmed necrosis- provoked by excitotoxic treatment of cells (necroptosis)

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27
Q

High [Glu]

A
  • cell death by necrosis- characterized by lysis due to osmotic swelling
  • involves both NMDA and non-NMDA receptors
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28
Q

Lower [Glu]

A

Cell death by apoptosis (no lysis)

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29
Q

Amyotrophic Lateral Sclerosis (ALS)

A

Motor neuron disease caused by excitotoxicity

  • Treatment: Riluzole- reduces Glu release
30
Q

Excitotoxic brain damage: domoic acid

A

Toxin made up of several species of marine algae

31
Q

NMDA receptors are involved in 2 forms of cell death

A

Apoptosis

Programmed necrosis

32
Q

Apoptosis

A
  • capsase- dependent
  • cell shrinkage
  • DNA cleavage
  • Phagocytosis of debris
33
Q

Programmed necrosis

A
  • capable-independent
  • GluN2B- dependent
  • extrasynaptic location
34
Q

[…] is a leading cause of death

A
  • loss of blood supply to the brain
  • ischemic (occlusion)
  • hemorrhagic
  • O2 deprivation
35
Q

O2 Deprivation (hypoxia)

A

Ischemic core

     - brain tissue that’s completely deprived of oxygen rapidly dies
     - ischemia- interruption of blood flow to brain due to excitotoxic brain damage

Penumbra- area of partial deprivation surrounding the core

36
Q

Loss of blood/ O2 initiated cell death

A
  1. Loss of ATP
  2. Pumps fail (Na+/K+ ATPase)
    - loss of ionic gradient
    - cell swelling/ rupture
    - membrane depolarization
  3. Increased neuronal firing
    - excessive Glu release
    - NMDA-R activation
    - voltage-gated Ca2+ channel activation
  4. Increased Ca2+ influx
    - Ca2+- activated protease and lipases
    - Free radical production
  5. Cell death (programmed necrosis)
37
Q

Treatment of stroke damage is largely unsuccessful

A

Restore blood supply
Block Ca2+ influx
Promote Glu clearance

*Severe side-effects (eg. Psychosis)- too much time elapses between stroke and treatment

38
Q

Restore blood supply

A
  • Thrombolytics (TPA)

- Anticoagulants (heparin, warfarin)

39
Q

Block Ca2+ influx

A
  • NMDA receptor blockers
    - Glycine site
    - PCP site
  • voltage-gated Ca2+ channels blockers
40
Q

Promote Glu clearance

A

Increase EAAT2 expression or function

41
Q

Drugs that block GABA synthesis

A

Allyglycine, thiosemicarbazide, 3-mercaptopropanoic acid

42
Q

GABA is found in […]

A

Cerebral cortex, hippocampus, substantia nigra

  • also cerebellum, striatum, globus pallidus, and olfactory bulbs
  • can be found in local interneurons and projection neurons (carry info longer distances)
  • only has job as NT and is manufactured by only GABAergic neurons
43
Q

GABA is the most abundant […] NT in the brain

A

GABA is the most abundant inhibitory NT in the brain

44
Q

CNS depressants

A
  • Anxiolytics
  • Anesthetics
  • Sedatives
  • Anticonvulsants
    - Tiagabine (Gabitril)
    - Vigabatrin (Sabril)
45
Q

Tiagabine (Gabritril)

A

Selective inhibitory of GAT-1

  • increases extracellular GABA levels
  • increased GABA transmissions
46
Q

Vigabratrin (Sabril)

A

Irreversible inhibitor of GABA-T

- prevents GABA metabolism and leads to buildup of GABA in brain

47
Q

GABA precursor

A

Glutamate—> GABA

Enzyme: Glutamic acid decarboxylase (GAD)

48
Q

GABA packaging enzyme

A

Vesicular GABA transporter (VGAT)

  • same transporter used to load Gly into synaptic vesicles
  • sometimes referred to as VIAAT (vesicular inhibitory amino acid transporter)
49
Q

GABA is coreleased with […]

A

GABA is coreleased with Gly, ACh, DA, and Glu
- coexpression of multiple vesicular transporters must take place (ex VIAAT and VAChT)

*Inhibitory neurons in CNS may release GABA only, Gly only, or both

50
Q

GABA transporters

A

GAT-1 and GAT-2- found in both neurons and astrocytes

GAT-3- astrocytes

51
Q

GAT-1

A

Can be found in astrocytes and at nerve terminals of GABAergic neurons: important for GABA reuptake

52
Q

GABA—> Glutamate

A

Enzyme: GABA amino-transferase (GABA-T)
Location: astrocytes and neurons

  • final product: succinate
  • byproduct: glutamate
  • in astrocytes, further synthesized to glutamine (using glutamine synthetase) and transported back to nerve terminal via glutamine transporters)
53
Q

GABAa ionotropic receptors are permeable to […] causing […]

A

GABAa ionotropic receptors are permeable to Cl- causing hyperpolarization

54
Q

GABAa ionotropic receptor subunits

A

5 subunits

2 a, 2 B, 1 g

Dominant type: (a1)2(B2)2(g2)
Extrasynaptic receptors: (a4)2(Bx)2(d) OR (a6)2(Bx)2(d)
- d binds neurosteroids and anesthetics
- further away from release site on postsynaptic neuron

55
Q

GABAa ionotropic receptor ligands

A
  • muscimol (agonist)
  • Bucucculine (comp antagonist)- convulsant
  • Picrotoxin, PTZ (non- competitive antagonist)
56
Q

GABA subunit binds on […] subunit

A

GABA subunit binds on B subunit

57
Q

a5 subunit is expressed most in […]

A

a5 subunit is expressed most in hippocampus

58
Q

Many CNS depressants are […] of GABAa receptors

A

Many CNS depressants are allosteric modulators of GABAa receptors

59
Q

Positive allosteric modulators of GABAa

A
  • Benzodiazepines
  • Barbituates
  • Ethanol, anesthetics, and neurosteroids
60
Q

Benzodiazepines

A

Binding requires g2 subunit (a-g interface)

Increases potency of GABA

      - Increases affinity of GABA for B-subunit
      - increases probability channel will open
      - increases Cl- influx
      - increases hyperpolarization
  • ex. Diazepam (Valium)- no effect on its own, but makes GABAergic response stronger
61
Q

Behavioral effects of alpha subunits of benzodiazepines

A

a1- sedation

  - enhancement of tonic cellular inhibition
   - zolpidem (Ambien)

a2/a3: anxiolytic
- alprazolam (Xanax): most selective anxiolytic substance)

a5- amnestic
- found in hippocampus

*low levels: reduce anxiety
High levels: sedation

62
Q

Barbituates

A

Habit forming, lethal in overdose (addiction potential)

Binding site:

  • on B-subunit distinct from GABA/ agonist site
    - increases Cl- flux
    - increases channel open probability
    - increases duration of channel opening
    - can function in absence of agonist
63
Q

Ethanol

A

Enhance GABAa receptor activity

64
Q

Anesthetics

A

Includes voltage-gated ion channels and ligand-gated ion channels

  • propofol (Diprivan)
  • a5- amnestic
65
Q

Neurosteroids

A
  • Steroid hormones synthesized in brain that act locally on GABAa receptor
  • Binding site on d-subunit, converts GABA from partial agonist to full agonist (extrasynaptic receptor)

Ex. Allopregnanolone (Zulresso) used in post-partum depression, allotetrahydrodeoxycorticosterone, and androstanediol

66
Q

Negative allosteric modulators

A

Picrotoxin, pentylenetetrazol (PTZ)

*convulsants

67
Q

GABAb receptors are […]

A

GABAb receptors are metabotropic

68
Q

Postsynaptic GABAb receptors

A
  • open K+ channels

- inhibition of cAMP

69
Q

Presynaptic GABAb receptors

A
  • autoreceptors, heteroreceptors
  • inhibition of Ca2+ channels
  • inhibition of cAMP
70
Q

GABAb agonist

A

Baclofen (Lioresal)

  • muscle relaxant and anti spastic agent
71
Q

GABAb antagonist

A

Competitive antagonist: Saclofen and 2- hydroxysaclofen

Neuropharmacology (15 decks)

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