In vivo/ex vivo and behavioural study on central effects of 5-HT1B/1D and 5-HT1A antagonists in guinea pigs.
Serotonin 5-HT1A and 5-HT1B/1D receptors control serotonin (5-HT) release and are targets for the pharmacological treatment of psychiatric disorders. We investigated effects of the 5-HT1B/1D antagonist GR127935, the 5-HT1A antagonist WAY 100635 and a combination of both in guinea pigs on the behaviour in the forced swimming test and on extracellular 5-HT in the hippocampus and the prefrontal cortex using in vivo microdialysis. Tissue content of 5-HT, 5-HIAA and 5-HT turnover (ratio 5-HIAA/5-HT) were determined in a sample containing i) the median and dorsal raphe nuclei, ii) the frontal cortex, or iii) the ventral hippocampus ex vivo. BEHAVIOUR: Administration of WAY 100635 (0.3-3.0 mg/kg, i.p.) or GR127935 (1.0-10.0 mg/kg, i.p.) or the combination of both delayed immobility in the forced swim test. MICRODIALYSIS: Systemic administration of WAY 100635 (1 mg/kg i.p.), perfusion with GR127935 (10 microM perfused into the frontal cortex) in the medial prefrontal cortex or the combination of both treatments had no significant effect on extracellular 5-HT. 5-HT TISSUE CONTENT AND 5-HT TURNOVER IN THE TISSUE: Compared to controls, WAY 100635, GR127935 and the combination thereof, decreased cortical 5-HT (-30%), increased 5-HIAA and consequently 5-HT turnover in the cortex threefold and the raphe nuclei twofold. WAY 100635 decreased 5-HT in the hippocampus (-40%), too. WAY 100635 and GR127935 and their combination increased hippocampal 5-HIAA and 5-HT turnover twofold, compared to controls. The results suggest that both 5-HT1 antagonists have subtle effects on 5-HT function under resting conditions; combined treatment has no superior effects compared to solitary treatment.
Rex
A
A
Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, Koserstr. 20, 14195 Berlin, Germany. rex.andre@vetmed.fu-berlin.de <rex.andre@vetmed.fu-berlin.de>
Voigt
J P
JP
Wicke
K M
KM
Fink
H
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D003863:Depression / Q000523:psychology; D005260:Female; D006168:Guinea Pigs; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D017551:Microdialysis; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects*; D044346:Receptor, Serotonin, 5-HT1D / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013550:Swimming / Q000523:psychology
D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090701:GR 127935; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide