GABAB RECEPTOR MODULATION OF ADENYLATE-CYCLASE ACTIVITY IN RAT-BRAIN SLICES

  • 1 January 1985
    • journal article
    • research article
    • Vol. 84  (1) , 249-257
Abstract
An investigation of the effects of GABA and the selective GABAB receptor agonists, baclofen, on basal and stimulated (cAMP) levels in slices of rat cerebral cortex was carried out. Neither GABA nor baclofen produced any significant change in basal cAMP levels. By contrast noradenaline [norepinephrine, NE] and forskolin both produced dose-dependent increases in cellular cAMP accumulation. GABA (in the presence of nipecotic acid) and baclofen both potentiated the maximal response to NE with baclofen (100 .mu.M) increasing the level of cAMP produced by NE (100 .mu.M) by 133%. GABA (0.3-100 .mu.M) was less effective than baclofen, increasing the response to NE by 70% at 100 .mu.M. (-)-Baclofen was the active isomer with (+)-baclofen failing to potentiate NE responses. Bicuculline-methobromide (100 .mu.M) failed to block the action of either GABA or baclofen. The enhancement of adrenoceptor-stimulated cAMP 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 cAMP levels. Thus(-) baclofen (100 .mu.M) 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 Na (40 mM) incubation medium, GABA also attenuated the rise in cAMP induced by 10 .mu.M forskolin. GABA produced little effect in normal Krebs solution.