title: 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 gamma-aminobutyric acid (GABA). However, the effect on [3H]IP2 accumulation was much greater than that on [3H]IP1 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 greater than 1 mM. Prazosin (1 microM) blocked the noradrenaline-induced formation of all three inositol phosphates (IPs), in both the presence and the absence of 2 mM GABA. 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 microM 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]IP2 content was less than that of [3H]IP1 content.
authors.affiliation: Department of Pharmacology, University of Cambridge, England.
authors.forename: M L
authors.initials: ML
authors.lastname: Crawford
authors.forename: J M
authors.initials: JM
authors.lastname: Young
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D004357:Drug Synergism; D018756:GABA Antagonists; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D018756:GABA Antagonists; D007295:Inositol Phosphates; D010743:Phospholipids; D011963:Receptors, GABA-A; D007294:Inositol; D005680:gamma-Aminobutyric Acid; D008094:Lithium; D009638:Norepinephrine