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

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.