Contribution of presynaptic GABA-B receptors to paired-pulse depression of GABA-responses in the hippocampus.
The synaptic release of gamma-aminobutyric acid (GABA) is thought to be regulated by presynaptic GABA receptors of the B-type. It was the goal of this study to validate this concept electrophysiologically using four selective antagonists of GABA-B receptors. Experiments were performed in hippocampal slices exposed to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX 30 microM) and D-2-amino-5-phosphonopentanoate (AP5 40 microM) in order to block excitatory transmission. Consequently, electrical stimulation of the Schaffer collateral/commissural fibers evoked monosynaptic inhibitory potentials (IPSP) recorded intracellularly from CA 1 pyramidal neurons. In a test called paired-pulse paradigm two identical stimuli were applied at intervals ranging from 350 to 4000 ms. The IPSP evoked by the second stimulation was smaller in its amplitude over the entire interval range. This reduction of the second GABA-response is thought to result from the activation of presynaptic GABA receptors. The GABA-uptake inhibitor SKF 89976 (100 microM) increased the amplitude of the IPSP's and increased the ratio of the first to the second IPSP amplitude. These findings indicate that the drug increases the GABA content in the synaptic cleft leading to a facilitation of paired-pulse depression. The actions of four bath-applied GABA-B receptor antagonists were examined in the paired-pulse paradigm. None of these compounds abolished paired-pulse inhibition completely even at concentrations higher than those required to block postsynaptic GABA-B responses. The potent GABA-B antagonists CGP 55845 and CGP 52432 reduced paired-pulse depression by 80% at 10 microM (maximal effect).(ABSTRACT TRUNCATED AT 250 WORDS)
Olpe
H R
HR
Research and Development Department, Pharmaceuticals Division, Ciba-Geigy Ltd., Basel, Switzerland.
Steinmann
M W
MW
Greiner
K
K
Pozza
M F
MF
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D004594:Electrophysiology; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000502:physiology; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000502:physiology
D001596:Benzylamines; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D011412:Propanolamines; D018080:Receptors, GABA-B; D017661:Receptors, Presynaptic; C086109:3-aminopropyl-cyclohexylmethylphosphinic acid; C083008:CGP 52432; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; C085075:CGP 55845A