Abstract
The synaptic release of γ-aminobutyric acid (GABA) is thought to be regulated by presynaptic GABA receptors of the 13-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 μM) and d-2-amino-5-phosphonopentanoate (AP5 40 μM) 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 GABAresponse is thought to result from the activation of presynaptic GABA receptors. The GABA-uptake inhibitor SKF 89976 (100 μM) 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 GABAB 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 μM (maximal effect). The other two compounds, CGP 46381 and CGP 36742 had no significant or only a subtle effect respectively.
The adenosine receptor antagonist, caffeine (100 μM) and the metabotropic excitatory amino acid receptor antagonist (1SS, 3 R)-1-aminocyclopentane-t,3-dicarboxylic acid (MCPG, 1 mM) had no effect on paired-pulse depression in the presence of CGP 55845 (10 μM)
In conclusion since all CGP compounds are GABA-B antagonists at postsynaptic sites these findings suggest that there may be differences between the pre- and postsynaptic GABA-B receptors. Apart from presynaptic GABA-B receptors there appear to exist additional mechanisms involved in paired-pulse depression that remain to be elucidated.
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Correspondence to: H.-R. Olpe at the above address
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Olpe, HR., Steinmann, M.W., Greiner, K. et al. Contribution of presynaptic GABA-B receptors to paired-pulse depression of GABA responses in the hippocampus. Naunyn-Schmiedeberg's Arch Pharmacol 349, 473–477 (1994). https://doi.org/10.1007/BF00169135
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DOI: https://doi.org/10.1007/BF00169135