Combined administration of a 5-hydroxytryptamine (5-HT)1D antagonist and a 5-HT reuptake inhibitor synergistically increases 5-HT release in 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 autoreceptor blockade on the increase in extracellular 5-HT levels produced by a selective 5-HT reuptake inhibitor (SSRI). Administration of the selective 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-hydroxyindoleacetic acid to 135% of basal values. Moreover, at these doses GR127935 significantly attenuated the decrease in extracellular 5-HT levels 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 basal levels. The combination of this low dose of sertraline with either dose of GR127935 resulted in a pronounced, long-lasting increases in 5-HT levels to 230% of basal values. These results indicate that the effects of an SSRI on terminal 5-HT are significantly enhanced by coadministration of a 5-HT1D antagonist and confirm that in addition to somatodendritic 5-HT1A autoreceptors, terminal 5-HT1D autoreceptors mitigate the effect of SSRIs 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 SSRIs.
Rollema
H
H
Central Research Division, Pfizer, Groton, Connecticut 06340-1596, USA.
Clarke
T
T
Sprouse
J S
JS
Schulz
D W
DW
D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D004357:Drug Synergism; D006168:Guinea Pigs; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D009474:Neurons / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline
D015057:1-Naphthylamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006897:Hydroxyindoleacetic Acid; D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C101999:CP 135807; C090701:GR 127935