Role of uptake in gamma-aminobutyric acid (GABA)-mediated responses in guinea pig hippocampal neurons.
Intracellular recordings were obtained from hippocampal pyramidal neurons maintained in vitro. Measurements were made of the conductance change induced by iontophoretically applied gamma-aminobutyric acid (GABA) and, using voltage-clamp techniques, of inhibitory postsynaptic currents resulting from activation of inhibitory pathways. Analysis of GABA iontophoretic charge-response curves indicated that there was considerable variation among neurons with respect to the slope of this relation. The placement of the GABA-containing pipette did not appear to be responsible for the observed variation, since vertical repositioning of the pipette did not alter the slope of the charge-response relationship. Steady iontophoresis of GABA from one barrel of a double-barreled pipette markedly affected the charge-response relation obtained when short pulses were applied to the other barrel. The curve was shifted to the left, and the slope was decreased. Concomitantly, the enhanced GABA-induced responses were prolonged. Similar alterations in GABA responsiveness were observed when the uptake blocker, nipecotic acid, was iontophoretically applied. Furthermore, bath application of saline containing a reduced sodium concentration (25% of control) also produced a prolongation of GABA-mediated responses. Under voltage clamp, inhibitory postsynaptic currents were observed to have biphasic decays. The initial, fast decay was prolonged by an average of 18% by nipecotic acid, whereas the later, slow phase was prolonged by 23%. The results of these studies support the hypothesis that a saturable GABA uptake system is responsible for the observed variation in the charge-response curves and, in turn, underlies the apparent sensitizing effect of excess GABA application. The results also suggest that a reduction of transmitter uptake affects the time course of inhibitory postsynaptic currents in the hippocampus.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D007478:Iontophoresis; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D013569:Synapses / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology*
D009557:Nipecotic Acids; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline