Investigations on GABAB receptor-mediated autoinhibition of GABA release.

In this study, we have investigated the effects of phaclofen on the [3H] overflow from [3H]GABA prelabelled rat cortical slices and its interaction with the effects of (-)-baclofen in dependence of the stimulation frequency. (-)-Baclofen strongly depressed the [3H] overflow in the frequency range of 0.125 to 4 Hz to a constant residual level (IC50 = 0.37 micromol/l at 0.125 Hz), but became inactive above. The potency of the (+)-enantiomer was considerably weaker by a factor of nearly 1000. The GABAB antagonist, phaclofen, increased [3H] overflow at 300 micromol/l and, more-markedly, at 3 and 1 mmol/l, respectively. However, the increase was virtually independent of the frequency between 0.125 and 16 Hz. If the compound interacted only with the putative GABAB autoreceptor involved in the regulation of GABA release, the extent of the enhancing effect should increase with increasing frequency because of the concomitant rise in synaptic GABA concentration. In order to further investigate this phenomenon, the IC50 of (-)-baclofen and antagonism of phaclofen against (-)-baclofen were determined at 0.125 Hz and 2 Hz, respectively. Whereas the IC50 of (-)-baclofen was 0.63 +/- 0.04 micromol/l at 0.125 Hz, it increased to 4.88 +/- 0.45 micromol/l at 2 Hz. The pA10-values of phaclofen were about the same at both frequencies, whereas the pA2-values differed by a factor of 2.3.(ABSTRACT TRUNCATED AT 250 WORDS)