The effect of SB‐269970, a 5‐HT 7 receptor antagonist, on 5‐HT release from serotonergic terminals and cell bodies

The presence of 5‐HT 7 receptor mRNA and protein in 5‐HT neurons suggests that this receptor may act as a 5‐HT autoreceptor. In this study, the effect of the 5‐HT 7 receptor antagonist, SB‐269970 ((R)‐1‐[3‐hydroxy phenyl)sulfonyl]‐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 nucleus (DRN), using the techniques of in vitro [ 3 H]‐5‐HT release or fast cyclic voltammetry, respectively. Cortical slices were loaded with [ 3 H]‐5‐HT and release was evoked by electrical stimulation. 5‐CT inhibited the evoked release of [ 3 H]‐5‐HT in a concentration‐dependent manner. SB‐269970 had no significant effect on [ 3 H]‐5‐HT release while the 5‐HT 1B receptor antagonist, SB‐224289 significantly potentiated [ 3 H]‐5‐HT release. In addition, SB‐269970 was unable to attenuate the 5‐CT‐induced inhibition of release while SB‐224289 produced a rightward 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. Rat DRN slices were electrically stimulated and the evoked 5‐HT efflux detected 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 efflux per se or 8‐OH‐DPAT‐induced inhibition of 5‐HT efflux. In addition, 5‐CT inhibited 5‐HT efflux in a concentration‐dependent manner. SB‐269970 was unable to attenuate the 5‐CT‐induced inhibition of 5‐HT efflux. In conclusion, we were unable to provide evidence to suggest a 5‐HT autoreceptor role for 5‐HT 7 receptors. However, investigations with more selective 5‐HT 7 receptor agonists are needed to confirm the data reported here.British Journal of Pharmacology (2001) 132 , 1574–1580; doi: 10.1038/sj.bjp.0703979