C. Roberts et al., The effect of SB-269970, a 5-HT7 receptor antagonist, on 5-HT release fromserotonergic terminals and cell bodies, BR J PHARM, 132(7), 2001, pp. 1574-1580
1 The presence of 5-HT7 receptor mRNA and protein in 5-HT neurons suggests
that this receptor may act as a 5-HT autoreceptor. In this study, the effec
t of the 5-HT7 receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulf
onyl]-2-[(2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on
5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nuc
leus (DRN), using the techniques of in vitro [H-3]-5-HT release or fast cyc
lic voltammetry, respectively.
2 Cortical slices were loaded with [H-3]-5-HT and release was evoked by ele
ctrical stimulation. 5-CT inhibited the evoked release of [H-3]-5-HT in a c
oncentration-dependent manner. SE-269970 had no significant effect on [H-3]
-5-HT release while the 5-HT1B receptor antagonist, SB-224289 significantly
potentiated [H-3]-5-HT release. In addition, SE-269970 was unable to atten
uate the 5-CT-induced inhibition of release while SB-224289 produced a righ
tward shift of the 5-CT response, generating estimated pK(B) values of 7.8
and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively.
3 Rat DRN slices were electrically stimulated and the evoked 5-HT efflux de
tected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and
was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT e
fflux pet se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5
-CT inhibited 5-HT efflux in a concentration-dependent manner. SE-269970 wa
s unable to attenuate the 5-CT-induced inhibition of 5-HT efflux.
4 In conclusion, we were unable to provide evidence to suggest a 5-HT autor
eceptor role for 5-HT7 receptors. However, investigations with more selecti
ve 5-HT7 receptor agonists are needed to confirm the data reported here.