The effect of SB-236057-A, a selective 5-HT1B receptor inverse agonist, onin vivo extracellular 5-HT levels in the freely-moving guinea-pig

5-HT1B autoreceptors are involved in the control of extracellular 5-HT leve ls from both the terminal and cell body regions of serotonergic neurones. I n this study we report on the effect of a selective and potent 5-HT1B recep tor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4- oxadiazolyl-2-yl)biphenyl4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f] pi peridine] hydrochloride), on extracellular 5-HT levels in the cortex and de ntate gyrus of the freely-moving guineapig, using the technique of in vivo microdialysis. SB-236057-A had ca. 23% bioavailability following oral drug administration. In vivo hypothermia pharmacodynamic assays demonstrated it was brain penet rant with a duration of action in excess of 18 h. SE-236057-A (0.75 mg/kg p .o.) increased extracellular 5-HT levels in the dentate gyrus to a maximum of 167+/-7% of basal but had no effect in the frontal cortex. However, a sm all increase in cortical 5-HT levels (117 +/- 11% of basal) was evident at 2.5 mg/kg p.o. In addition, SE-236057-A (0.75 mg/kg and 2.5 mg/kg p.o.) ant agonised the sumatriptan-induced inhibition of extracellular 5-HT levels in the guinea-pig frontal cortex. These differences were attributed to MRN-in nervated regions (e.g. dentate gyrus) being more responsive to 5-HT1B recep tor-mediated negative feedback than DRN-innervated regions (e.g. frontal co rtex). In the dentate gyrus, the increase in 5-HT release induced by SE-236 057-A (0.75 mg/kg p.o.) was comparable to that after 14 days of paroxetine (10 mg/kg p.o.) administration, reaching a maximum of 183 +/- 13% of basal. These data suggest that acute 5-HT1B receptor blockade, by virtue of incre ased 5-HT release in the dentate gyrus, may provide a rapidly acting antide pressant.