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

Abstract

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.

Functional Characterization of 5-HT1BReceptor Drugs in Nonhuman Primates Using Simultaneous PET-MR

“…Human 5-HT 1B Rs display consti-tutive activity when expressed in recombinant cell systems, and compounds such as methiothepin, SB-224289, and SB-236057-A decrease basal GTP␥S activity, indicating that they are inverse agonists (Pauwels et al, 1998;Roberts et al, 2001). However, evidence of these inverse agonist properties has not been confirmed in vivo (Roberts et al, 2001;Stenfors and Ross, 2002). Our results also match other studies conducted in vitro and in vivo that found that although GR127935 itself has little effect, it can block the anti-aggressive effect of 5-HT 1B R agonists (Doménech et al, 1997;Bannai et al, 2007).…”