POTENTIAL MECHANISMS INVOLVED IN THE NEGATIVE COUPLING BETWEEN SEROTONIN 5-HT1A RECEPTORS AND CARBACHOL-STIMULATED PHOSPHOINOSITIDE TURNOVER IN THE RAT HIPPOCAMPUS

被引:37
作者
CLAUSTRE, Y [1 ]
BENAVIDES, J [1 ]
SCATTON, B [1 ]
机构
[1] SYNTHELABO RECH,BIOCHEM PHARMACOL GRP,31 AVE PAUL VAILLANT COUTURIER,F-92220 BAGNEUX,FRANCE
关键词
SEROTONIN 5-HT1A RECEPTORS; PHOSPHOINOSITIDE TURNOVER; HIPPOCAMPUS; DEVELOPING RAT; CARBACHOL; 8-HYDROXY-2-(DI-N-PROPYLAMINO)TETRALIN; PROTEIN KINASE-C; PHOSPHOLIPASE A2; H-3]QUINUCLIDINYL BENZYLATE BINDING;
D O I
10.1111/j.1471-4159.1991.tb11422.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10-mu-M)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) > ipsapirone (20) > gepirone (120) > RU 24969 (140) > buspirone (560) > 1-(m-trifluoromethylphenyl)piperazine (1,500) > methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10-mu-M) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1-mu-M), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10-mu-M forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10-mu-M) and arachidonic acid (100-mu-M). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10-mu-M quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100-mu-M), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor. The latter possibility is supported by the fact that incubation of immature rat hippocampal slices with 8-OH-DPAT (10-mu-M) caused a down-regulation (-16%) of [H-3]quinuclidinyl benzylate binding.
引用
收藏
页码:1276 / 1285
页数:10
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