Dual mechanisms of GABAA response inhibition by beta-lactam antibiotics in the pyramidal neurones of the rat cerebral cortex.
1. The effects of beta-lactam antibiotics on the gamma-aminobutyric acid (GABA)-induced Cl- current were investigated in pyramidal neurones freshly dissociated from the rat frontal cortex by the use of a nystatin-perforated patch recording mode under voltage-clamp conditions. 2. The GABA-induced inward current increased in a concentration-dependent manner with an EC50 of 6.7 x 10(-6) M at a holding potential of -40 mV. The GABA response was accompanied by an increase in the membrane conductance and reversed at near the Cl- equilibrium potential. 3. All beta-lactams (penicillin, imipenem, aztreonam and cefotiam) inhibited the 10(-5) M GABA-induced response in a concentration-dependent manner with an IC50 and Hill coefficient of 1.3 x 10(-3) M and 0.64 for penicillin, 9.6 x 10(-4) M and 0.83 for imipenem, 2.5 x 10(-3) M and 9.99 for aztreonam, and 2.9 x 10(-4) M and 1.03 for cefotiam. 4. Imipenem inhibited the GABA-response competitively while penicillin inhibited the same response in a noncompetitive fashion. 5. The inhibitory action of imipenem showed no voltage-dependency, whereas the effect of penicillin was voltage-dependent. 6. It is thus proposed that some classes of beta-lactams, including imipenem may have a mechanism that is different from penicillin and competitively affects the GABAA receptor.
Fujimoto
M
M
Department of Physiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Munakata
M
M
Akaike
N
N
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001398:Aztreonam / Q000494:pharmacology; D015310:Cefotiam / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects*; D058787:GABA-A Receptor Antagonists; D015378:Imipenem / Q000494:pharmacology; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D010400:Penicillin G / Q000494:pharmacology; D010406:Penicillins / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D018118:Chloride Channels; D058787:GABA-A Receptor Antagonists; D010406:Penicillins; D015378:Imipenem; D015310:Cefotiam; D001398:Aztreonam; D010400:Penicillin G