The effect of SB-236057-A, a selective 5-HT1B receptor inverse agonist, on in vivo extracellular 5-HT levels in the freely-moving guinea-pig.
5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurones. In this study we report on the effect of a selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl- 1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydros piro [furo[2,3-f]indole-3,4' -piperidine] hydrochloride), on extracellular 5-HT levels in the cortex and dentate gyrus of the freely-moving guinea-pig, 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 penetrant with a duration of action in excess of 18 h. SB-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 small increase in cortical 5-HT levels (117+11% of basal) was evident at 2.5 mg/kg p.o. In addition, SB-236057-A (0.75 mg/kg and 2.5 mg/kg p.o.) antagonised the sumatriptan-induced inhibition of extracellular 5-HT levels in the guinea-pig frontal cortex. These differences were attributed to MRN-innervated regions (e.g. dentate gyrus) being more responsive to 5-HT1B receptor-mediated negative feedback than DRN-innervated regions (e.g. frontal cortex). In the dentate gyrus, the increase in 5-HT release induced by SB-236057-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 increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.
Roberts
C
C
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK. Claire_Roberts-1@sbphrd.com
Hatcher
P
P
Hagan
J J
JJ
Austin
N E
NE
Jeffrey
P
P
Wyman
P
P
Gaster
L M
LM
Routledge
C
C
Middlemiss
D N
DN
D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007035:Hypothermia / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology
D007211:Indoles; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; C121558:SB 236057; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D018170:Sumatriptan