Gamma- Amino- Butyric- Acid  (GABA)
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Gamma- Amino- Butyric- Acid (GABA) Before 1883 known as a metabolite of plants and microorganisms (Basidio-, Streptomycetes) 1883 synthesized 1949 identified in animal tissue not incorporated in proteins !!! 1956 first indications on an inhibitory activity on

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Gamma- Amino- Butyric- Acid (GABA)

Before 1883 known as a metabolite of plants

and microorganisms (Basidio-, Streptomycetes)

1883 synthesized

1949 identified in animal tissue

not incorporated in proteins !!!

1956 first indications on an inhibitory activity on

nervous tissue

Inhibitory GABA-Rs in Crustaceans

in periphery (strech receptor) and CNS

main inhibitory fuctions in the vertebrate CNS


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γ-AminoButyricAcid (GABA)

Praesynapse: Glutamat

GAD

GABA

_______________________________________________

Synapt. Cleft Transporter EAAT 3,4

_______________________________________________

Postsynapse

Inhibitory R Ionotropic: GABA A und C

-Receptor

binding sites for

GABA, benzodiazepines, barbiturates

metabotropic: GABA B-Rezeptor


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GABA receptors

GABAA

GABAC

GABAB

ionotropic

metabotropic

benzodiazepine site

GABA site

Selective agonists

muscimol

Diazepam

L-baclofen

---

---

Inverse agonists

DMCM

β-carbo

lines

2-hydorxy-s-(-)-saclofen

Selective antagonists

bicuculline (6.0)

flumazenil

picrotoxin

Neuropharmacology Uni-Tuebingen


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Anatomy

Whole CNS Exclusively in CNS in vertebrates

most common inhibition mediating

transmitter.

All CNS neurons are bearing

GABA receptors

Cortex Interneurons in local cell assemblies

Basal Ganglia interneurons

projecting neurons


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CORTEX

GLU

GLU

GLU

GABA

GABA

THAL

STRIATUM

ACH

SNr

D1(+)

GPi

GPe

D2(-)

GABA

GABA

GABA

DA

GABA

GABA

GLU

SNc

STN

GLU

DA


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Physiology of GABA

Inhibition throughout the CNS of vertebrates

Regulation of neuronal excitability

of learning

of anxiety


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Pathophysiology of GABA

Reduced GABA-activity

in local cell assemblies: Overexcitability / Epilepsy

In striatal output neurons: Chorea Huntington

Enhanced GABA-activity

In local cell assemblies: reduced excitability

inhibition of learning

anxiolytic

anesthetic


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LIGANDS AT GABA-RECEPTORS

1. GABA – site of GABAA-REC.

agonist

antagonist

MUSCIMOL

pro-convulsive

BICUCULLIN

(cordyalis lutea = Lerchensporn)

(BARBITURATES)

Th: former hypnotics

antiepileptic

narcotic

PICROTOXIN

(anamyrta cocculus = Scheinmyrte)


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EXKURS:

TOXINS of amanita muscaria

MUSCIMOL

amanita muscaria

non-GABAergic compounds:

ibotenic acid

(NMDA-R-agonist)

muscarin

(M-AChR-agonist)


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LIGANDS AT GABA-RECEPTORS

Th: hypnotic (MIDAZOLAM, FLUNITRAZEPAM)

antiepileptic / anticonvulsive (CLONAZEPAM, DIAZEPAM)

anxiolytic (DIAZEPAM)

myotonolytic (TETRAZEPAM)

addictive

hang over

Th: hypnotic

anxiolytic

less addictive?

2. BDZ – site of GABAA-REC. (BZ1 & BZ2)

agonists

antagonist

ACTION

OF

GABA

plus

BENZODIAZEPINS

IMIDAZOPYRIDINES

(Zolpidem)


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LIGANDS AT GABA-RECEPTORS

Th: antidot

pro-convulsive

2. BDZ – site of GABAA-REC. (BZ1 & BZ2)

agonists

antagonist

ACTION

OF

GABA

plus

minus

inverse agonists

BENZODIAZEPINS

FLUMAZENIL

IMIDAZOPYRIDINES

(Zolpidem)

-CARBOLINES

(-CCB)


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LIGANDS AT GABA-RECEPTORS

3. GABAB – receptor

agonist

antagonist

BACLOFEN

SACLOFEN

Th: muscle relaxant


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BENZODIAZEPINS

DIAZEPAM (VALIUM)

CNS

LIVER

desmethyldiazepam

OXAZEPAM


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BENZODIAZEPINS

DIAZEPAM (VALIUM)

MIDAZOLAM

(DORMICUM)

CNS

LIVER

OH-mdz

mdz-glucuronid

desmethyldiazepam

OXAZEPAM


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BENZODIAZEPINS

DIAZEPAM (VALIUM)

MIDAZOLAM

(DORMICUM)

t1/2=32h

t1/2=3h !

desmethyldiazepam

t1/2=50-100h

OXAZEPAM

t1/2=8h

t1/2=2h


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GABA T – or GABA-transporter – inhibition

Na Valproate

Vigabatrine

= gamma vinyl GABA

Th: antiepileptics


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