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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
Author(s) -
Rollema Hans,
Clarke Thomas,
Sprouse Jeffrey S.,
Schulz David W.
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.67052204.x
Subject(s) - autoreceptor , reuptake inhibitor , microdialysis , serotonin , agonist , endocrinology , 5 ht receptor , medicine , serotonin reuptake inhibitor , antagonist , pharmacology , chemistry , biology , receptor , central nervous system
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‐HT 1D 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‐HT 1D 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 increase 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‐HT 1D antagonist and confirm that in addition to somatodendritic 5‐HT 1A autoreceptors, terminal 5‐HT 1D autoreceptors mitigate the effect of SSRIs on terminal 5‐HT. As such, antagonists of the 5‐HT 1D autoreceptor could be useful as rapidly acting antidepressants and may shorten the onset of antidepressant action when combined with SSRIs.