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5-HT1B/1D- and 5-HT1A antagonists: central 5-HT release and turnover
Objectives: Serotonin 5-HT1A and 5-HT1B/1D receptors control serotonin (5-HT) release in the CNS. They are targets for the pharmacological treatment of psychiatric disorders.
Methods: We investigated effects of the 5-HT1B/1D antagonist GR127935 (10 µM perfused into the frontal cortex), the 5-HT1A antagonist WAY100635 (1 mg/kg i.p.) and a combination of both on cortical 5-HT release in guinea pigs using in vivo microdialysis in comparison to reference drugs as the 5-HT releaser d-fenfluramine and the 5-HT1A agonist 8-OH-DPAT. The tissue content of 5-HT and 5-HT turnover (5-HIAA/5-HT ratio) was also determined in brain regions ex vivo.
Results: 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 and 5-HT turnover: 5-HT and 5-HT turnover were determined in a sample containing i) the median and dorsal raphe nuclei, ii) the frontal cortex or iii) the ventral hippocampus. Compared to controls WAY100635, GR127935 and the combination thereof, decreased cortical 5-HT (-30%), and increased 5-HT turnover in the cortex (270%) as well as in the raphe nuclei (180%). 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.
Conclusions: 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.