Repeated administration of the 5-HT1B receptor antagonist SB-224289 blocks the desensitisation of 5-HT1B autoreceptors induced by fluoxetine in rat frontal cortex

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Abstract
Desensitisation of 5-HT1A and 5-HT1B 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-HT1B 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-HT1B autoreceptors in frontal cortex, as measured by the action of CP 93129 (10 μM) to reduce 5-HT levels, was prevented by concomitant administration of the 5-HT1B receptor antagonist SB 224289 (2.5 mg/kg s.c.). 5-HT1B receptor activity in hypothalamus and 5-HT1A 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-HT1B autoreceptor antagonists are administered acutely together with SSRIs may not be maintained after repeated administration.

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