gamma-Aminobutyric acid inhibition of histamine-induced inositol phosphate formation in guinea-pig cerebellum: comparison with guinea-pig and rat cerebral cortex.
1. gamma-Aminobutyric acid (GABA), 2 mM, inhibited basal accumulation of [3H]-inositol monophosphate ([3H]-IP1) in lithium-treated slices of guinea-pig cerebellum preincubated with [3H]-inositol. In contrast, 2 mM GABA stimulated the accumulation of [3H]-IP1 in rat cerebral cortical slices over a 60 min incubation period, but had no significant effect in slices of guinea-pig cerebral cortex. The estimated IC50 for the inhibitory action of GABA in guinea-pig cerebellar slices was 0.52 +/- 0.12 mM. 2. GABA inhibited histamine-induced [3H]-IP1 accumulation in guinea-pig cerebellar slices in a non-competitive manner. The best-fit value for the maximum level of inhibition was 74 +/- 6%. The estimated IC50 for GABA was 0.77 +/- 0.15 mM and was not significantly different from the IC50 for inhibition of the basal accumulation of [3H]-IP1. The response to histamine in guinea-pig and rat cerebral cortical slices was also inhibited by 2 mM GABA. 3. In guinea-pig cerebellar slices 2 mM GABA potentiated histamine-induced [3H]-inositol bisphosphate ([3H]-IP2) accumulation, whereas in both guinea-pig and rat cerebral cortex the effect was inhibition. 4. Isoguvacine and muscimol, GABAA-selective agonists, and (-)-baclofen, GABA(B)-selective, had no significant effect on basal or histamine-stimulated accumulation of [3H]-IPs in guinea-pig cerebellar slices. (-)-Baclofen had only a weak inhibitory effect on [3H]-IP1 accumulation in guinea-pig-cerebral cortex (16 +/- 6% inhibition with 10 microM (-)-baclofen), whereas in rat cerebral cortex (-)-baclofen mimicked the inhibitory effect of GABA. 5. Nipecotic acid (1 mM) had qualitatively similar effects to those of 2mm GABA in guinea-pig cerebellar slices. 6. The competitive GABA uptake inhibitors SK&F 89976-A, SK&F 100330-A and SK&F 100561-A were potent histamine H,-receptor antagonists, as indicated by the inhibition of [3H]-mepyramine binding to homogenates of guinea-pig cerebellum and cerebral cortex. 7. GABA (2 mM) caused a small inhibition (12 + 3%) of [3H]-inositol incorporation into total inositol phospholipids in guinea-pig cerebellar slices, as in rat cerebral cortical slices, whereas 0.2mm histamine caused a small stimulation (15 + 4%). In the presence of both GABA and histamine, [3H]-inositol incorporation was unchanged from basal (101 + 5%). 8. GABA also inhibited [3H]-IP1 formation induced by endothelin-1 in guinea-pig cerebellar slices and increased, but not significantly, the amount of [3H]-IP2 accumulated. This, taken with the inhibitory effect on basal and histamine-stimulated accumulation, suggests that the action of GABA in guinea-pig cerebellar slices may be non-selective and may not be exerted through a specific GABA receptor.
Department of Pharmacology, University of Cambridge.
M L
ML
Crawford
H
H
Carswell
J M
JM
Young
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology; D018756:GABA Antagonists; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D011738:Pyrilamine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000502:physiology
D016232:Endothelins; D018756:GABA Antagonists; D007295:Inositol Phosphates; D010743:Phospholipids; D005680:gamma-Aminobutyric Acid; D006632:Histamine; D008094:Lithium; D011738:Pyrilamine