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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
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
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
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
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
Physiology of GABA Inhibition throughout the CNS of vertebrates Regulation of neuronal excitability of learning of anxiety
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
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)
EXKURS: TOXINS of amanita muscaria MUSCIMOL amanita muscaria non-GABAergic compounds: ibotenic acid (NMDA-R-agonist) muscarin (M-AChR-agonist)
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)
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)
LIGANDS AT GABA-RECEPTORS 3. GABAB – receptor agonist antagonist BACLOFEN SACLOFEN Th: muscle relaxant
BENZODIAZEPINS DIAZEPAM (VALIUM) CNS LIVER desmethyldiazepam OXAZEPAM
BENZODIAZEPINS DIAZEPAM (VALIUM) MIDAZOLAM (DORMICUM) CNS LIVER OH-mdz mdz-glucuronid desmethyldiazepam OXAZEPAM
BENZODIAZEPINS DIAZEPAM (VALIUM) MIDAZOLAM (DORMICUM) t1/2=32h t1/2=3h ! desmethyldiazepam t1/2=50-100h OXAZEPAM t1/2=8h t1/2=2h
GABA T – or GABA-transporter – inhibition Na Valproate Vigabatrine = gamma vinyl GABA Th: antiepileptics