Cocaine and lidocaine have additive inhibitory effects on the GABA(A) current of acutely dissociated hippocampal pyramidal neurons

Inhibition mediated by gamma-aminobutyric acid (GABA) is a major target for the central actions of cocaine and lidocaine, which can result in seizures , especially when these drugs are abused in combination. In the present stu dy, we investigated how cocaine and lidocaine interact to depress GABA curr ent (I-GABA), recorded by the whole-cell technique in freshly isolated rat hippocampal neurons. Cocaine depressed I-GABA in a concentration dependent manner, such that cocaine was mole potent against lower than higher GABA co ncentrations: the cocaine IC50 was 0.13, 0.62 and 1.2 mM for GABA at 2, 10 and 100 mu M, respectively. Cocaine depressed I-GABA to the same extent in the absence and presence of 1 mu M tetrodotoxin, indicating that cocaine in hibition of I-GABA is distinct from its Na+ channel blocking action. Lidoca ine reversibly depressed I-GABA evoked by 10 mu M GABA, with an IC50 of 9.8 mM. In the presence of 3 mM lidocaine, 0.3 mM cocaine depressed I-GABA (10 mu M GABA) to 30 +/- 7%. The significantly greater depression by the combi ned agents (p < 0.05) indicates additive effects on the GABA receptor/chann el complex, which are Likely to contribute to the additive convulsant effec ts noted when these drugs are abused in combination. (C) 1999 Elsevier Scie nce B.V. All rights reserved.