Desensitisation of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin re-uptake inhibitors (SSRIs) when these are administered chronically, while blockade of these autoreceptors occurring on administration of an SSRI together with an autoreceptor antagonist is responsible for the acute increase in 5-HT levels in vivo observed under these circumstances. The effects of repeated administration of SSRIs together with 5-HT(1B) receptor antagonists on 5-HT levels and autoreceptor activity have not been studied previously with an in vivo method. In this work we found, using in vivo microdialysis that the effect of fluoxetine (5 mg/kg i.p. daily for 7 days) to desensitise 5-HT(1B) autoreceptors in frontal cortex, as measured by the action of CP 93129 (10 microM) to reduce 5-HT levels, was prevented by concomitant administration of the 5-HT(1B) receptor antagonist SB 224289 (2.5 mg/kg s.c.). 5-HT(1B) receptor activity in hypothalamus and 5-HT(1A) autoreceptor activity, as determined by the effects of s.c. 8-OH-DPAT to reduce 5-HT levels, were not altered either by fluoxetine alone at this dose or by fluoxetine in the presence of SB 224289. We conclude that the effects obtained when 5-HT(1B) autoreceptor antagonists are administered acutely together with SSRIs may not be maintained after repeated administration.