Potentiation of GABA(A) receptor agonists by GABA uptake inhibitors in therat ventral midbrain

Whole-cell patch recordings were made from dopamine-containing neurons in t he ventral tegmental area (VTA) and substantia nigra zona compacta (SNC). I soguvacine evoked an outward current (at - 60 mV) in a concentration-depend ent manner with an EC50 of 62 +/- 8 muM. The gamma -aminobutyric acid (GABA ) uptake inhibitor 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrah ydro-3-pyridine-carboxylic acid hydrochloride (NO 711) (3 muM) shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 22 +/- 4 muM. L-Arginine (3 mM) also shifted the isoguvacine concentration-re sponse curve to the left. with a new EC50 of 29 +/- 5 muM. L-Arginine (3 mM ) increased the currents evoked by GABA (100 muM) and muscimol (1 muM) by 2 08% and 261%, respectively, The GABA uptake inhibitor 4,5,6.7,-tetrahydrois oxazolo[4,5-c]-pyridin-3-ol hydrobromide (THPO) (300 muM) not only mimicked but also occluded the ability Of L-arginine (3 mM) to potentiate currents evoked by isoguvacine. Equimolar replacement of Na+ with choline increased GABA-evoked currents, suggesting that a low Na+ concentration has an inhibi tory effect on GABA transport. Low Na+ concentration (25 mM) inhibited isog uvacine currents but still occluded the potentiating effects of L-arginine. We conclude that GABA uptake inhibitors potentiate the actions of the GABA (A) receptor agonists, isoguvacine and muscimol, probably because they are effective substrates for GABA transporters in the ventral midbrain. (C) 200 1 Elsevier Science B.V. All rights reserved.