GABAB receptor modulation of adenylate cyclase activity in rat brain slices.
An investigation of the effects of gamma-aminobutyric acid (GABA) and the selective GABAB receptor agonist, baclofen, on basal and stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in slices of rat cerebral cortex has been carried out. Neither GABA nor baclofen produced any significant change in basal cyclic AMP levels. By contrast noradrenaline and forskolin both produced dose-dependent increases in cellular cyclic AMP accumulation. GABA (in the presence of nipecotic acid) and baclofen both potentiated the maximal response to noradrenaline with baclofen (100 microM) increasing the level of cyclic AMP produced by noradrenaline (100 microM) by 133%. GABA (0.3-100 microM) was rather less effective than baclofen, increasing the response to noradrenaline by 70% at 100 microM. (-)-Baclofen was the active isomer with (+)-baclofen failing to potentiate noradrenaline responses. Bicuculline-methobromide (100 microM) failed to block the action of either GABA or baclofen. The enhancement of adrenoceptor-stimulated cyclic AMP accumulation persisted in the presence of a phosphodiesterase inhibitor (1 mM 3-isobutyl-1-methylxanthine) and also in Ca2+-free solution. When forskolin was used to stimulate adenylate cyclase, the effect of baclofen was to inhibit the rise in cyclic AMP levels. Thus (-)-baclofen (100 microM) shifted the dose-response curve to forskolin to the right 5 fold in an apparently parallel fashion. The effect was again stereospecific for the (-)-isomer of baclofen. When GABA uptake was reduced using low sodium (40 mM) incubation medium, GABA also attenuated the rise in cyclic AMP induced by 10 microM forskolin. GABA produced little effect in normal Krebs solution.
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005576:Colforsin; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D066298:In Vitro Techniques; D009557:Nipecotic Acids / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D004224:Diterpenes; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D001418:Baclofen; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine