Premium
γ‐Aminobutyric acid inhibition of histamine‐induced inositol phosphate formation in guinea‐pig cerebellum: comparison with guinea‐pig and rat cerebral cortex
Author(s) -
Crawford Melissa L.A.,
Carswell Heather,
Young J.M.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14106.x
Subject(s) - guinea pig , histamine , cerebral cortex , cerebellum , inhibitory postsynaptic potential , medicine , inositol phosphate , muscimol , endocrinology , inositol , baclofen , chemistry , biology , agonist , biochemistry , receptor
1 γ‐Aminobutyric acid (GABA), 2m m , inhibited basal accumulation of [ 3 H]‐inositol monophosphate ([ 3 H]‐IP 1 ) in lithium‐treated slices of guinea‐pig cerebellum preincubated with [ 3 H]‐inositol. In contrast, 2m m GABA stimulated the accumulation of [ 3 H]‐IP 1 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 IC 50 for the inhibitory action of GABA in guinea‐pig cerebellar slices was 0.52 ± 0.12 m m . 2 GABA inhibited histamine‐induced [ 3 H]‐IP 1 accumulation in guinea‐pig cerebellar slices in a noncompetitive manner. The best‐fit value for the maximum level of inhibition was 74 ± 6%. The estimated IC 50 for GABA was 0.77 ± 0.15 m m and was not significantly different from the IC 50 for inhibition of the basal accumulation of [ 3 H]‐IP 1 . The response to histamine in guinea‐pig and rat cerebral cortical slices was also inhibited by 2 m m GABA. 3 In guinea‐pig cerebellar slices 2m m GABA potentiated histamine‐induced [ 3 H]‐inositol bisphosphate ([ 3 H]‐IP 2 ) accumulation, whereas in both guinea‐pig and rat cerebral cortex the effect was inhibition. 4 Isoguvacine and muscimol, GABA A ‐selective agonists, and (−)−baclofen, GABA B ‐selective, had no significant effect on basal or histamine‐stimulated accumulation of [ 3 H]‐IPs in guinea‐pig cerebellar slices. (−)−Baclofen had only a weak inhibitory effect on [ 3 H]‐IP 1 accumulation in guinea‐pig‐cerebral cortex (16 + 6% inhibition with 10 μ m (−)−baclofen), whereas in rat cerebral cortex (−)−baclofen mimicked the inhibitory effect of GABA. 5 Nipecotic acid (1 m m ) had qualitatively similar effects to those of 2m m 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 1 ‐receptor antagonists, as indicated by the inhibition of [ 3 H]‐mepyramine binding to homogenates of guinea‐pig cerebellum and cerebral cortex. 7 GABA (2m m ) caused a small inhibition (12 ± 3%) of [ 3 H]‐inositol incorporation into total inositol phospholipids in guinea‐pig cerebellar slices, as in rat cerebral cortical slices, whereas 0.2 m m histamine caused a small stimulation (15 ± 4%). In the presence of both GABA and histamine, [ 3 H]‐inositol incorporation was unchanged from basal (101 ± 5%). 8 GABA also inhibited [ 3 H]‐IP 1 formation induced by endothelin‐1 in guinea‐pig cerebellar slices and increased, but not significantly, the amount of [ 3 H]‐IP 2 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.