DIFFERENTIAL-EFFECTS OF GABAERGIC LIGANDS IN MOUSE AND RAT HIPPOCAMPAL-NEURONS

Previous electrophysiological studies suggested that GABA(A) receptors in rat hippocampal neurons might be less sensitive to ethanol than mouse neurons. Therefore, we examined the effects of ethanol (0.5-850 mM) in cultured mouse (C57BL/6) and rat (Sprague-Dawley) neurons. In 35% of the mouse neurons, the Cl- current was potentiated by ethanol starting at 0.5 mM. In all of the rat neurons examined, on the other hand, the current was potentiated by concentrations starting at 200 mM. We also studied the effects of GABA and other GABAergic ligands. GABA(A) receptors in rat and mouse neurons displayed EC(50)s for GABA of 9 +/- 0.3 and 17 +/- 0.8 mu M, respectively and ethanol did not significantly change these values. The EC(50) for diazepam was 92 +/- 3 and 120 +/- 8 nM in rat and mouse, respectively. Pentobarbital enhanced the current with EC(50)s of 84 +/- 3 and 106 +/- 6 mu M in rat and mouse, respectively. The sensitivity for Cl-218,872, which binds preferentially to the Type I benzodiazepine receptor, was similar in all the neurons. RO 15-4513, an inverse partial agonist to the benzodiazepine receptor, was not effective in reversing the potentiation of the Cl- current in rat neurons and only slightly reduced the potentiation in mouse neurons. The receptors in rat neurons were more sensitive to external Zn2+; the current was inhibited by 50% with a concentration of 93 +/- 3 and 244 +/- 9 mu M in rat and mouse, respectively. Analysis of mRNA encoding for the gamma 2L receptor subunit showed similar levels in rat and mouse neurons. The data suggest that most pharmacological properties of hippocampal GABA(A) mouse and rat receptors are comparable, with the exception of the sensitivity to ethanol and Zn2+. These differences can not be explained by differential expression of gamma 2L subunits. We provide good experimental evidence indicating a difference in the sensitivity of the GABA(A) receptor to GABAergic ligands in two distinct animal species.