Interaction of ethanol and allosteric modulators with GABAA-activated currents in adult medial septum/diagonal band neurons.
Behavioral and electrophysiological studies suggest that neurons in the medial septum may express ethanol sensitive GABAA receptors. In the present study, patch-clamp recordings of whole-cell currents were used to directly characterize the ethanol sensitivity of GABAA receptors on acutely dissociated neurons, isolated from the medial septum/nucleus of the diagonal band (MS/nDB) of the adult rat brains. MS/nDB neurons displayed inward currents in response to GABA applied rapidly with a large-bore dual pipette system. The currents were mediated by the activation of GABAA receptors, since they reversed near the calculated reversal potential for chloride and were completely blocked by bicuculline. GABA responses were concentration dependent with an EC50 of 8.7 microM GABA and a slope of 1.35 suggesting cooperativity. Pharmacologically relevant concentrations of ethanol (3-300 mM) neither significantly increased nor decreased mean responses to GABA in neurons from Sprague Dawley or High Alcohol Sensitivity (HAS) rats. Mean GABA currents were significantly increased by 300 mM ethanol in neurons from 'ethanol sensitive' Fischer 344, ACI and Wistar Kyoto inbred rats. In subsets of neurons, 12.5 to 57.1% of those tested from these 5 rats strains, ethanol (30-300 mM) significantly increased GABA currents by > or = 20%. An additional, 10 percent of cells from Sprague Dawley rats showed ethanol-induced inhibition of GABA-activated current by < or = 20%. Allosteric modulators pentobarbital (10 microM), midazolam (1 microM) and lanthanum (300 microM), enhanced, while zinc (30 microM) decreased GABA-activated currents in all neurons, consistent with the well-known actions of these agents. These results suggest that GABAA receptors on MS/dDB neurons are pharmacologically similar to those on other neurons with respect to regulation by allosteric modulators. On the other hand, ethanol sensitivity of GABAA receptors varies considerably from cell to cell ranging from significant enhancement to inhibition of GABA-activated current.
Frye
G D
GD
Department of Medical Pharmacology and Toxicology, Texas A & M University, College of Medicine, College Station 77843-1114.
Fincher
A S
AS
Grover
C A
CA
Griffith
W H
WH
D000494:Allosteric Regulation; D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects*; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D008874:Midazolam / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D012688:Septum Pellucidum / Q000166:cytology / Q000187:drug effects*; D015032:Zinc / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D007811:Lanthanum; D010424:Pentobarbital; D015032:Zinc; D008874:Midazolam