Changes in extracellular K+ evoked by GABA, THIP and baclofen in the guinea-pig hippocampal slice.
Changes in [K+]0 evoked by the inhibitory amino acid transmitter, GABA (gamma-aminobutyric acid) and its agonists were recorded with ion-selective microelectrodes in the CA1 stratum pyramidale of guinea-pig hippocampal slices. Bath applications of GABA (0.1-10 mM) produced dose-dependent increases in [K+]0 (EC50 = 4 mM, Rmax = 1.6 mM), with a peak and decline during exposure, followed by undershoot during recovery. In contrast the selective GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo-(5,4-c)-pyridin-3-ol) (0.01-1 mM) showed approximately ten-fold greater potency and evoked only increases in [K+]0 (EC50 = 0.5 mM, Rmax = 2 mM). Reduction of temperature from 34 degrees to 22 degrees C caused a more than two-fold augmentation of the K+0 accumulation evoked by GABA, but no change in that due to THIP. The GABAA antagonist, BMI (bicuculline methiodide) (100 microM) completely blocked responses to THIP and partially antagonized those to GABA. Responses to GABA were synergistically enhanced by pentobarbital (100 microM). Only small, delayed and inconsistent changes could be evoked by relatively high concentrations of the GABAB agonist, DL-baclofen (0.01-1 mM). The K+ changes evoked by GABA appear to be mediated by the activation of GABAA receptors with low affinity and to be related to their depolarizing action. Although the response includes an electrogenic component which suggests the involvement of Na-dependent transmitter uptake/transport, the increase in K+0 probably reflects an outward counter/co-transport of K+ with Cl/HCO3 anion shifts and/or activation of a voltage-dependent K+ conductance.
Barolet
A W
AW
Department of Pharmacology, University of Toronto, Ont. Canada.
Morris
M E
ME
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004566:Electrodes; D018756:GABA Antagonists; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives*; D011963:Receptors, GABA-A / Q000187:drug effects; D013696:Temperature; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018756:GABA Antagonists; D007555:Isoxazoles; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline; D001418:Baclofen; C015542:gaboxadol; D011188:Potassium