COMBINED ADMINISTRATION OF A 5-HYDROXYTRYPTAMINE (5-HT)(1D) ANTAGONIST AND A 5-HT REUPTAKE INHIBITOR SYNERGISTICALLY INCREASES 5-HT RELEASEIN GUINEA-PIG HYPOTHALAMUS IN-VIVO
H. Rollema et al., COMBINED ADMINISTRATION OF A 5-HYDROXYTRYPTAMINE (5-HT)(1D) ANTAGONIST AND A 5-HT REUPTAKE INHIBITOR SYNERGISTICALLY INCREASES 5-HT RELEASEIN GUINEA-PIG HYPOTHALAMUS IN-VIVO, Journal of neurochemistry, 67(5), 1996, pp. 2204-2207
In vivo microdialysis in guinea pig hypothalamus was used to study the
effect of serotonin [5-hydroxytryptamine (5-HT)] subtype 1D autorecep
tor blockade on the increase in extracellular 5-HT levels produced by
a selective 5-HT reuptake inhibitor (SSRI). Administration of the sele
ctive 5-HT1D antagonist GR127935 at 0.3 mg/kg had no effect, but 5 mg/
kg significantly increased extracellular levels of 5-HT and 5-hydroxyi
ndoleacetic acid to 135% of basal values. Moreover, at these doses GR1
27935 significantly attenuated the decrease in extracellular 5-HT leve
ls following local perfusion with the selective 5-HT1D agonist CP-135,
807. The SSRI sertraline at 2 mg/kg increased 5-HT levels to 130% of b
asal levels. The combination of this low doss of sertraline with eithe
r dose of GR127935 resulted in a pronounced, long-lasting increase in
5-HT levels to 230% of basal values. These results indicate that the e
ffects of an SSRI on terminal 5-HT are significantly enhanced by coadm
inistration of a 5-HT1D antagonist and confirm that in addition to som
atodendritic 5-HT1A autoreceptors, terminal 5-HT1D autoreceptors mitig
ate the effect of SSRls on terminal 5-HT. As such, antagonists of the
5-HT1D autoreceptor could be useful as rapidly acting antidepressants
and may shorten the onset of antidepressant action when combined with
SSRls.