Failure to detect in vivo inverse agonism of the 5-HT(1B) receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs

Naunyn Schmiedebergs Arch Pharmacol. 2002 Jun;365(6):462-7. doi: 10.1007/s00210-002-0564-8. Epub 2002 Apr 18.


The possibility that 5-HT(1B) 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-HT(1B/1D) receptor agonist 3-( N-methylpyrrolidin-2- R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-1 H-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-HT(1B) autoreceptors were functionally active during reserpine treatment. The 5-HT(1B) 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-HT(1B) autoreceptors (5-HIAA formation) or 5-HT(1B) heteroreceptors (rectal temperature) could be detected under the in vivo experimental conditions used.

MeSH terms

  • Animals
  • Guinea Pigs
  • Male
  • Piperidones / pharmacology*
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin / metabolism*
  • Serotonin / deficiency*
  • Serotonin / metabolism
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*
  • Spiro Compounds / pharmacology*


  • Piperidones
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin
  • SB 22489G
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Spiro Compounds
  • Serotonin