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 the rank order of potency of 5-hydroxytrptamine (5-HT), 5-carboxamidotryptamine and sumatriptan for inhibition of electrically stimulated [3H]-5-HT release correlates well with published data on their 5-HT1D receptor binding affinities. 2 Both the non-selective 5-HT1D receptor antagonist, methiothepin and the selective 5-HT1D receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl]phenyl]-2'-methyl-4'- (5-methyl-1,2,4-oxadiazole-3-yl) [1,1-biphenyl]4-carboxamide (GR127935) increased stimulated [3H]-5-HT release per se and also attenuated agonist-induced inhibition of [3H]-5-HT release. GR127935 (10 nM-100 nM) produced a pA2 of 9.0 against 5-HT, which is consistent with its 5-HT1D receptor binding affinity. 3 From these findings we conclude that, in guinea-pig cerebral cortex, the 5-HT terminal autoreceptor is of the 5-HT1D receptor subtype. However, three observations suggest the presence of multiple terminal autoreceptors: shallow inhibition curves to the agonists; a shallow Schild slope of GR127935 antagonism and differences in the maximal responses to 5-HT between whole cortex and frontal cortex.
Roberts
C
C
Psychiatry Research Department, SmithKline Beecham Pharmaceuticals, Harlow, Essex.
Watson
J
J
Burton
M
M
Price
G W
GW
Jones
B J
BJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D010455:Peptides; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D012701:Serotonin; D008719:Methiothepin; D018170:Sumatriptan; C047087:5-carboxamidotryptamine