The ability of WAY100,635 to potentiate the neurochemical and functional actions of fluoxetine is enhanced by co-administration of SB224,289, but not BRL15572

The present study employed a combined neurochemical and behavioural approach to address the question of whether blockade of (presynaptic) 5-HT1B or 5-HT1D receptors enhances the facilitatory influence of 5-HT1A, autoreceptor antagonism upon the actions of selective serotonin re-uptake inhibitors (SSRI). In the presence of the selective 5-HT1A antagonist, WAY 100,635, the fluoxetine-induced increase in dialysate levels of 5-HT in the frontal cortex (FCX) of freely-moving rats was significantly potentiated. The selective 5-HT1B antagonist, SB224,289, likewise potentiated the increase in 5-HT levels evoked by fluoxetine. Further, administered together, WAY100,635 and SB224,289, at least additively, potentiated the influence of fluoxetine upon 5-HT levels. This effect was selective inasmuch as, either alone or together, WAY100,635 and SB224,289 did not modify the influence of fluoxetine upon FCX levels of dopamine (DA) or noradrenaline (NA) quantified in the same dialysis samples. Co-administration of SB224,289 also enhanced the ability of WAY100,635 to potentiate the induction of head-twitches (HTW) by fluoxetine. This response reflects activation of 5-HT2A sites in FCX and was abolished by the selective 5-HT2A antagonist, MDL100,907. In contrast to SB224,289, the 5-HT,, antagonist, BRL15572, failed to enhance the facilitatory influence of WAY100,635 upon the neurochemical or behavioural actions of fluoxetine. In conclusion, co-joint blockade of 5-HT1B - but not 5-HT1D - with 5-HT1A autoreceptors markedly potentiates the neurochemical and functional actions of the SSRI, fluoxetine. (C) 2000 Elsevier Science Ltd. All rights reserved.