Ethanol differentially modulates GABAA receptor-mediated chloride currents in hippocampal, cortical, and septal neurons in rat brain slices.
Previous electrophysiological studies have reported conflicting results concerning the effects of ethanol on gamma-aminobutyric acid-A (GABAA) receptor-mediated responses in the brain. To examine the variables that might explain these inconsistencies, the present study was designed to determine whether ethanol modulation of synaptically evoked GABA responses is brain region dependent, to identify factors that might regulate ethanol sensitivity, and to investigate the mechanism(s) underlying ethanol modulation of GABA responses. Whole-cell voltage clamp methods were used to examine the effects of ethanol on synaptically evoked GABAA inhibitory postsynaptic currents (IPSCs) recorded from neurons in hippocampus, cerebral cortex, and intermediate lateral and medial septum from rat brain slice preparations. Bicuculline-sensitive IPSCs elicited by local stimulation were pharmacologically isolated by pretreatment with the glutamate specific antagonists, DL-(-)-2-amino-5-phosphonovaleric acid (APV) and 6, 7-dinitroquinoxaline-2, 3-dione (DNQX). Superfused ethanol (80 mM) potentiated evoked GABAA IPSCs in cortical neurons and in intermediate lateral and medial septal neurons but not in CA1 hippocampal neurons. However, the mechanism by which ethanol enhanced GABAA IPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABAA IPSC reversal potential (EIPSC) without modifying the underlying GABAA receptor-mediated conductance (GIPSC). In contrast, ethanol enhanced GABAA IPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABAA IPSC reversal potential (EIPSC) without modifying the underlying GABAA receptor-mediated conductance (GIPSC). In contrast, ethanol enhanced GABAA IPSC amplitudes in lateral and medial septal neurons by increasing the GIPSC without modifying the EIPSC. These results suggest that ethanol differentially modulates responses to endogenous GABA released during synaptic activation and that important differences between various brain regions may reflect multiple mechanisms of ethanol action.
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80220.
B L
BL
Soldo
W R
WR
Proctor
T V
TV
Dunwiddie
D000818:Animals; D001921:Brain / Q000166:cytology; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D000431:Ethanol / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013569:Synapses / Q000502:physiology
D018118:Chloride Channels; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D000431:Ethanol