FUNCTIONAL-CHARACTERIZATION OF THE 5-HT TERMINAL AUTORECEPTOR IN THE GUINEA-PIG BRAIN CORTEX

1 In guinea-pig cerebral cortical slices in vitro we have shown that t he rank order of potency of 5-hydroxytryptamine (5-HT), 5-carboxamidot ryptamine and sumatriptan for inhibition of electrically stimulated [H -3]-5-HT release correlates well with published data on their 5-HT1D r eceptor binding affinites. 2 Both the non-selective 5-HT1D receptor an tagonist, methiothepin and the selective 5-HT1D receptor antagonist, y -3-(4-methyl-1-piperazinyl][phenyl]-2'-methyl-4'- (5-methyl,1,2,4-oxad iazole-3-yl) [1,1-biphenyl]4-carboxamide (GR127935) increased stimulat ed [H-3]-5-HT release per se and also attenuated agonist-induced inhib ition of [3H]-5-HT release. GR127935 (10 nM-100 nM) produced a pA(2), of 9.0 against 5-HT, which is consistent with its 5-HT1D receptor bind ing affinity. 3 From these findings we conclude that, in guinea-pig ce rebral cortex, the 5-HT terminal autoreceptor is of the 5-HT1D recepto r subtype. However, three observations suggest the presence of multipl e terminal autoreceptors: shallow inhibition curves to the agonists; a shallow Schild slope of GR127935 antagonism and differences in the ma ximal responses to 5-HT between whole cortex and frontal cortex.