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Failure to detect in vivo inverse agonism of the 5-HT1B receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs

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Abstract.

The possibility that 5-HT1B receptors display constitutive activity in vivo, i.e. have a basal agonist-independent activity, was examined in guinea-pigs depleted of endogenous brain 5-HT by pre-treatment with reserpine. Under these conditions (5 mg/kg s.c. reserpine 24 h before the experiment), hypothalamic 5-HT concentration was reduced by more than 97%. In reserpine-treated animals, 5-HT synthesis [measured as the accumulation of 5-hydroxytryptophan (5-HTP) after inhibition of the aromatic amino acid decarboxylase with m-hydroxybenzylhydrazine dihydrochloride (NSD 1015, 100 mg/kg s.c.)] was similar to that in non-treated guinea-pigs. The formation of 5-hydroxyindoleacetic acid (5-HIAA) was enhanced by reserpine treatment. The 5-HT1B/1D receptor agonist 3-(N-methylpyrrolidin-2-R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-1H-indole (CP-135,807) decreased 5-HT synthesis and 5-HIAA formation to the same extent in reserpine-treated and naive animals showing that the terminal 5-HT1B autoreceptors were functionally active during reserpine treatment. The 5-HT1B inverse agonist 1′-methyl-5-([2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl)-4-yl]carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4′-piperidine] hydrochloride (SB-224289, 4 mg/kg s.c.), which in naive guinea-pigs significantly enhanced 5-HIAA formation and tended to enhance 5-HT synthesis, had no effect in the reserpine-treated animals. Likewise, SB-224289 did not change the rectal temperature in reserpine-treated guinea-pigs although the agonist CP-135,807 had a significant hypothermic effect in these animals. It is concluded that no constitutive activity of 5-HT1B autoreceptors (5-HIAA formation) or 5-HT1B heteroreceptors (rectal temperature) could be detected under the in vivo experimental conditions used.

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Stenfors, C., Ross, S.B. Failure to detect in vivo inverse agonism of the 5-HT1B receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs. Naunyn-Schmiedeberg's Arch Pharmacol 365, 462–467 (2002). https://doi.org/10.1007/s00210-002-0564-8

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  • DOI: https://doi.org/10.1007/s00210-002-0564-8

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