POTENTIATION BY GAMMA-AMINOBUTYRIC-ACID OF ALPHA-1-AGONIST-INDUCED ACCUMULATION OF INOSITOL PHOSPHATES IN SLICES OF RAT CEREBRAL-CORTEX

Abstract: Noradrenaline‐induced accumulation of 3H‐labeled inositol mono‐, bis‐, and trisphosphate (IP1, IP2, and IP3, respectively) in lithium‐treated slices of rat cerebral cortex preincubated with [3H]inositol was potentiated by γ‐aminobutyric acid (GABA). However, the effect on [3H]IP3 accumulation was much greater than that on [3H]IP3 or [3H]IP3 accumulation. The principal effect of GABA on noradrenaline concentration–response curves for both [3H]IP1 and [3H]IP2 was to cause an increase in the maximal response attainable. However, whereas the EC50 for GABA potentiation of [3H]IP1 formation was 0.5 mM, the curve for the potentiation of [3H]IP2 formation showed a marked upturn at GABA concentrations of >1 mM. Prazosin (1 μM) blocked the noradrenaline‐induced formation of all three inositol phosphates (IPs), in both the presence and the absence of 2 mMGABA. 3H‐IP formation induced by phenylephrine and methoxamine was also potentiated by GABA, and again the greatest effect was on [3H]IP2 accumulation. The ratio of [3H]IP2/[3H]IP1 formed in response to 100 μM noradrenaline was increased by 2 mM GABA at all times from 10 to 60 min, whereas the ratio of [3H]IP3/[3H]IP1 was little altered. The effect of GABA was not mimicked by the GABAA agonists isoguvacine and 3‐aminopropanesulphonic acid and was not blocked by bicuculline methiodide. (–)‐Baclofen, a GABAB agonist, did produce some stimulation of the response to noradrenaline, but to a much lesser extent than GABA. Of the agents tested, nipecotic acid came nearest to reproducing the effect of GABA, in that the major effect was on [3H]IP2 accumulation. The effects of 2 mM GABA and 2 mM nipecotic acid were not additive. GABA potentiation of noradrenaline‐induced 3H‐IP formation was still apparent in the absence of Li+, but the increase of [3H]IP content was less than that of [3H]IP1 content. Copyright © 1990, Wiley Blackwell. All rights reserved