Latency to paroxetine-induced anxiolysis in the rat is reduced by co-administration of the 5-HT1A receptor antagonist WAY100635

1 We report here the use of rat high-light social interaction to model the temporal anxiolytic/antidepressant effects of SSRIs seen in the clinic. Compared to vehicle controls, 21, but not 14, days of paroxetine treatment (3 mg kg(-1), p.o., daily) produced a marked increase in rat social interaction (Vehicle = 71.3+/-7.3 s; Paroxetine = 116.7+/-14.7 s; P<0.01) with no concurrent effect on locomotor activity, consistent with anxiolysis. 2 To assess whether concurrent 5-HT1A receptor blockade reduces the time to onset of anxiolysis seen with paroxetine alone (21 days), rats were implanted with osmotic minipumps to continuously infuse the 5-HT1A receptor antagonist WAY100635 (1 mg kg(-1) day(-1) s.c., 7 days) alone or in combination with paroxetine (3 mg kg-l, p.o., daily, 7 days), prior to anxiety testing. Paroxetine (Veh/Par=61.9+/-7.9 s) or WAY100635 (WAY/Veh=71.6+/-4.7 s) alone, had no effect on social interaction time compared to vehicle treated controls (Veh/Veh=76.4+/-4.9 s), whilst coadministration of WAY100635 with paroxetine, produced a marked elevation in social interaction (WAY/Par=149.3+/-16.8 s; P<0.01) relative to all other groups with no concurrent change in locomotor activity. 3 In contrast, acute administration of WAY100635 (0.03 mg kg(-1) s.c.) with paroxetine (3 mg kg(-1), p.o.) did not alter any behavioural measure, suggesting that the anxiolysis induced by the combination after 7 days is attributable to a CNS adaptive response. 4 This data demonstrates that coadministration of a 5-HT1A receptor antagonist with paroxetine markedly reduces the latency to anxiolysis, in the rat. 5 This study supports the use of the rat social interaction test to further delineate adaptive changes in the CNS responsible for the anxiolytic/antidepressant action of SSRIs seen in humans.