AUTORECEPTOR-MEDIATED REGULATION OF GABA RELEASE - ROLE OF UPTAKE INHIBITION AND EFFECTS OF NOVEL GABA(B) ANTAGONISTS

Citation
Pc. Waldmeier et al., AUTORECEPTOR-MEDIATED REGULATION OF GABA RELEASE - ROLE OF UPTAKE INHIBITION AND EFFECTS OF NOVEL GABA(B) ANTAGONISTS, Naunyn-Schmiedeberg's archives of pharmacology, 347(5), 1993, pp. 514-520
Citations number
17
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00281298
Volume
347
Issue
5
Year of publication
1993
Pages
514 - 520
Database
ISI
SICI code
0028-1298(1993)347:5<514:AROGR->2.0.ZU;2-4
Abstract
While the role of GABA(B) autoreceptors in the regulation of GABA rele ase in synaptosomes and brain slices is well established, little is kn own about their role in vivo. Doubts have arisen because there is an a pparent discrepancy between the frequencies at which GABA neurons fire and the frequency range within which autoreceptor regulation is obser ved in vitro. To see whether this apparent mismatch could be due to th e use of a GABA uptake inhibitor in the release experiments in slices, we have compared the frequency dependencies of GABA release in the pr esence and absence of uptake inhibition. Beforehand, the previously in complete frequency curve in the presence of uptake inhibition was exte nded at the lower end. To achieve this, stimulation was performed by m eans of groups of 4 pseudo-one-pulses (POP's) at inter-POP intervals c orresponding to frequencies of 0.015625-0.5 Hz. It could be shown that activation of the GABA(B) autoreceptor by endogenously released GABA begins at a stimulation frequency as low as 0.0625 Hz. Experiments wit h 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 activa ted the autoreceptor. The frequency dependence in the absence as compa red to the presence of uptake inhibition was shifted towards higher fr equencies by a factor of 4. We do not consider this enough to remove o ur doubts about the in vivo operativity of GABA(B) autoreceptors. Furt her experiments in the presence of uptake inhibition were made to see whether the expectation was met that autoreceptor-mediated regulation of GABA release could be blocked out by sufficiently high concentratio ns of potent antagonists. As judged from the frequency dependence in t he presence of 1 mumol/l of the potent compound CGP 55845 as well as f rom the similarity of the maximal increases of GABA release caused at 0. 125 and 2 Hz by various other potent, novel GABA(B) antagonists, th is was not the case. Possible explanations are the occurrence of an ag onist and an antagonist state of the autoreceptor prevailing at low GA BA concentrations or, less likely, the occurrence of two autoreceptor subtypes with different relative sensitivities towards GABA and baclof en on the one hand and towards aminophosphonous acid antagonists on th e other. Finally, it was shown that also in the absence of uptake inhi bition, regulation of GABA release was mediated entirely by GABA(B) au toreceptors. Both muscimol and bicuculline at 1 and 10 mumol/l were wi thout effect.