Enhancement of 5-HT1B and 5-HT1D receptor antagonist effects on extracellular 5-HT levels in the guinea-pig brain following concurrent 5-HT1A or 5-HTre-uptake site blockade

The effects of selective serotonin re-uptake inhibitor (SSRI), paroxetine, and 5-HT1A, 5-HT1B and 5-HT1B/1D receptor antagonists on in vivo extracellu lar 5-HT levels in the guinea-pig frontal cortex and dorsal hippocampus wer e investigated using the technique of microdialysis, The aim of the study w as to further investigate the autoreceptor roles of the 5-HT1A, 5-HT1B and 5-HT1D receptors in the median vs dorsal raphe nuclei. In the frontal corte x, 5-HT1A (WAY 100635, 1 mg/kg i.p.) or 5-HT1B (SB-224289, 4 mg/kg i.p.) re ceptor antagonists had no effect on extracellular levels of 5-HT, whilst th e mixed 5-HT1B/1D receptor antagonist (GR 127935, 0.3 mg/kg i.p) produced a significant decrease in extracellular 5-HT levels. Paroxetine (10 mu M) si gnificantly increased extracellular 5-HT levels when perfused locally into the cortex. Administration of 3B-224289, followed 120 min later by WAY 1006 35, had no effect on extracellular 5-HT levels. In contrast, sequential adm inistration of either WAY 100635 and GR 127935, or SB-224289 and paroxetine significantly increased extracellular 5-HT levels. In the dorsal hippocamp us, whilst 5-HT1A receptor antagonism elicited by administration of WAY 100 635 had no effect, both 5-HT1B and mixed 5-HT1B/1D receptor blockade signif icantly increased extracellular 5-HT levels. Administration of SE-224289 fo llowed 120 min later with WAY 100635, or WAY 100635 followed 30 min later w ith GR 127935, potentiated the effect of the three compounds alone, signifi cantly increasing extracellular 5-HT levels. These data demonstrate that to simultaneously increase extracellular 5-HT in both frontal cortex and dors al hippocampus of the guinea-pig brain concurrent 5-HT1A, 5-HT1B and 5-HT1D receptor blockade is required. Whereas in the dorsal hippocampus, 5-HT1B r eceptor blockade is sufficient to elicit an increase in extracellular 5-HT levels. (C) 1999 Elsevier Science Ltd. All rights reserved.