Lanthanum and zinc sensitivity of GABAA-activated currents in adult medial septum/diagonal band neurons from ethanol dependent rats.
The impact of chronic ethanol treatment, sufficient to induce tolerance and physical dependence, on GABAA receptor function was studied in acutely isolated neurons from the medial septum/nucleus diagonal band (MS/nDB) of adult rats using whole cell, patch-clamp recordings. In ethanol-naive Controls, GABA (0.3-300 microM) induced concentration-dependent increases in Cl- current with a threshold of 0.3-1 microM, a mean maximal current of 7645 +/- 2148 pA at 100-300 microM, an EC50 of 11.3 +/- 1.3 microM and a slope of 1.53 +/- 0.07. GABA-activated currents in neurons from animals receiving two weeks of ethanol liquid diet treatment did not differ significantly on any of these measures. The rate of GABAA receptor desensitization (t1/2 = 6.49 +/- 1.19 s) estimated as the time required for loss of 50% of peak current during sustained application of 10 microM GABA, as well as the residual steady state current remaining following complete desensitization for controls was unchanged by chronic ethanol. The impact of chronic ethanol treatment on the GABAA receptor modulation by lanthanum and zinc which act as positive and negative allosteric modulators, respectively, was also evaluated. Test pulses of 3 microM GABA in control neurons showed maximal potentiation by 141 +/- 30% at approximately 1000 microM lanthanum with an EC50 of 107 +/- 34 microM and a slope of approximately 1. Lanthanum potentiation remained the same following chronic ethanol treatment. Initial estimates based on fitted concentration response curves suggested that maximal inhibition of 3 microM GABA responses by zinc at the level of 70.2 +/- 8.5% in control cells was significantly increased by chronic ethanol treatment to 95.3 +/- 2.5%, although the IC50 of 60.2 +/- 25 microM was not changed. However, this difference was not supported by direct tests of maximal 3-10 mM zinc concentrations. These results suggest that chronic ethanol treatment, sufficient to induce tolerance and physical dependence, probably does not lead to readily detectible changes in GABAA receptor function in MS/nDB neurons.
Frye
G D
GD
Department of Medical Pharmacology and Toxicology, Texas A & M University, College of Medicine 77843-1114, USA. gdfrye@tamu.edu
Fincher
A S
AS
Grover
C A
CA
Jayaprabhu
S
S
D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001923:Brain Chemistry / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007700:Kinetics; D007811:Lanthanum / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D015032:Zinc / Q000494:pharmacology*
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D007811:Lanthanum; D015032:Zinc