Pharmacopsychiatry 2005; 38 - A191
DOI: 10.1055/s-2005-918813

Effects of 5-HT1B/1D- and 5-HT1A antagonists on 5-HT release and turnover in the CNS

A Rex 1, JP Voigt 1, KM Wicke 2, H Fink 1
  • 1Institut für Pharmakologie und Toxikologie, Fachbereich Veterinärmedizin, Freie Universität Berlin, Berlin
  • 2Abbott Laboratories, Neuroscience Discovery Research, Ludwigshafen

5-HT1A and 5-HT1B/1D receptors regulate serotonin (5-HT) release in the CNS. They are pharmacological targets for treatment of psychiatric disorders.

We investigated effects of the 5-HT1B/1D antagonist GR127935 (10µM perfused into the cortex), the 5-HT1A antagonist WAY100635 (1mg/kg i.p.) and a combination of both on cortical 5-HT release in guinea pigs using in vivo microdialysis and on tissue content of 5-HT and 5-HT turnover (5-HIAA/5-HT ratio) in brain regions determined ex vivo.

Microdialysis: As references, the 5-HT releasing agent d-fenfluramine and the 5-HT1A agonist 8-OH-DPAT increased and decreased cortical 5-HT release, respectively. Systemic administration of WAY100635, perfusion with GR127935 in the frontal cortex or the combination of both treatments had no significant effect on extracellular 5-HT.

5-HT content: 5-HT and 5-HT turnover were determined in the nucleus raphe region, in the frontal cortex and the ventral hippocampus. WAY100635, GR127935 and the combination decreased cortical 5-HT (–30%), increased 5-HT turnover in the cortex (270%) and in the raphe (180%) compared to controls. WAY100635 decreased hippocampal 5-HT (–40%), while both drugs and their combination increased hippocampal 5-HT turnover (200%) compared to controls. Combined treatment had no superior or additive effects.

The region-specific decrease in 5-HT and the concomitant increase in local 5-HT turnover suggest that both 5-HT1 antagonists have subtle effects on 5-HT function.