Autoreceptor-mediated regulation of GABA release: role of uptake inhibition and effects of novel GABAB antagonists.
While the role of GABAB autoreceptors in the regulation of GABA release in synaptosomes and brain slices is well established, little is known about their role in vivo. Doubts have arisen because there is an apparent discrepancy between the frequencies at which GABA neurons fire and the frequency range within which autoreceptor regulation is observed in vitro. To see whether this apparent mismatch could be due to the use of a GABA uptake inhibitor in the release experiments in slices, we have compared the frequency dependencies of GABA release in the presence and absence of uptake inhibition. Before-hand, the previously incomplete frequency curve in the presence of uptake inhibition was extended at the lower end. To achieve this, stimulation was performed by means of groups of 4 pseudo-one-pulses (POP's) at inter-POP intervals corresponding to frequencies of 0.015625-0.5 Hz. It could be shown that activation of the GABAB autoreceptor by endogenously released GABA begins at a stimulation frequency as low as 0.0625 Hz. Experiments with the antagonist, CGP 35348, at inter-POP intervals of 1 min, at which the preceding POP has no longer an effect on GABA release during the next one, showed that basal release alone already substantially activated the autoreceptor. The frequency dependence in the absence as compared to the presence of uptake inhibition was shifted towards higher frequencies by a factor of 4. We do not consider this enough to remove our doubts about the in vivo operativity of GABAB autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Research Department, Ciba-Geigy AG, Basel, Switzerland.
P C
PC
Waldmeier
C
C
Hertz
P
P
Wicki
C
C
Grunenwald
P A
PA
Baumann
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004558:Electric Stimulation; D058787:GABA-A Receptor Antagonists; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D058787:GABA-A Receptor Antagonists; D009557:Nipecotic Acids; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; C066430:CGP 35348; D001640:Bicuculline