Potentiation of GABA(A) receptor agonists by GABA uptake inhibitors in the rat ventral midbrain.
Whole-cell patch recordings were made from dopamine-containing neurons in the ventral tegmental area (VTA) and substantia nigra zona compacta (SNC). Isoguvacine evoked an outward current (at -60 mV) in a concentration-dependent manner with an EC50 of 62+/-8 microM. The gamma-aminobutyric acid (GABA) uptake inhibitor 1-(2(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NO 711) (3 microM) shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 22+/-4 microM. L-Arginine (3 mM) also shifted the isoguvacine concentration-response curve to the left, with a new EC50 of 29+/-5 microM. L-Arginine (3 mM) increased the currents evoked by GABA (100 microM) and muscimol (1 microM) by 208% and 261%, respectively. The GABA uptake inhibitor 4,5,6,7,-tetrahydroisoxazolo[4,5-c]-pyridin-3-ol hydrobromide (THPO) (300 microM) 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 inhibitory effect on GABA transport. Low Na+ concentration (25 mM) inhibited isoguvacine 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.
Shen
K Z
KZ
Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland 97201, USA.
Johnson
S W
SW
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004357:Drug Synergism; D004594:Electrophysiology; D018755:GABA Agonists / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins; D058785:GABA-A Receptor Agonists; D066298:In Vitro Techniques; D007539:Isonicotinic Acids / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology; D027361:Organic Anion Transporters; D010091:Oximes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000502:physiology; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002352:Carrier Proteins; D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D058785:GABA-A Receptor Agonists; D007539:Isonicotinic Acids; D007555:Isoxazoles; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; C078793:NNC 711; C026804:4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridin-3-ol; D005680:gamma-Aminobutyric Acid; D012964:Sodium; C015300:isoguvacine