Evidence for accelerated desensitisation of 5-HT2C receptors following combined treatment with fluoxetine and the 5-HT1A receptor antagonist, WAY 100,635, in the rat

Both pre-clinical and clinical studies suggest that additional treatment with 5-HT1A receptor antagonists may accelerate the antidepressant efficacy/onset of selective serotonin re-uptake inhibitors (SSRIs). Given that chronic SSRI treatment has been shown to desensitise 5-HT2C receptor mediated responses, we have used the rat social interaction test to determine if combined treatment with WAY 100,635, a selective 5-HT1A receptor antagonist, will accelerate this effect. In pairs of unfamiliar rats, acute administration of the 5-HT2C receptor agonist m-chlorophenylpiperazine (mCPP) or fluoxetine decreased the time spent in social interaction, responses which were reversed by the 5-HT2C/2B receptor antagonists SE 200646A and SE 221284. Similar reductions in social interaction were observed in rats treated with fluoxetine (10 mg/kg, i.p. daily) for 4, 7 and 14 days but was no longer apparent after 28 days of treatment. in contrast, only 7 days of combined treatment with WAY 100,635 (I mg/kg/s.c./day) and fluoxetine were needed to reverse this response. The decrease in social interaction induced by an acute challenge of mCPP (1 mg/kg, i.p.) was also reduced after 6 days co-treatment with WAY 100,635 and fluoxetine. Thus, WAY 100,635 accelerates SSRI-induced desensitisation of 5-HT2C, receptors, suggesting that this response might contribute towards the therapeutic effects of SSRIs in man. (C) 2000 Elsevier Science Ltd. All rights reserved.