Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and 8-OH-DPAT-induced changes in the rat

5-HT1A receptor antagonists have recently been shown to accelerate the effe cts of some antidepressant drugs in clinical trials. In this study we inves tigate the effects of combining a full antagonist at the 5-MT1A receptor, W AY 100635 (0.2 mg/kg, SC) with the selective serotonin reuptake inhibitor ( SSRI) paroxetine (5 mg/kg, IP) in the olfactory bulbectomized (OB) rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in the open-field apparatus, following 3, 7, and 14 d ays of treatment. Further to the OB study, we simultaneously studied adapti ve changes in 5-MT1A receptor function, utilizing alterations in the hypoth ermic response to the 5-HT1A receptor agonist 8-OH-DPAT. Paroxetine, in com bination with WAY 100635, attenuated the hypothermic effects of 8-OH-DPAT a s early as 3 days, with a full reversal evident following 7 days, whereas p aroxetine, although attenuating the hypothermic effects in OB group by day 7, only reversed it fully after 14 days. Paroxetine alone and in combinatio n with the antagonist reversed the olfactory bulbectomy-induced hyperactivi ty in the open field following 14 days of treatment only, this being the no rmal time of an "antidepressant" response in this model. However, there was no significant attenuation at any of the earlier time points. This further demonstrates that the reversal of this aspect of the olfactory bulbectomy- induced behavioral syndrome is insensitive to the potential faster onset of antidepressant action induced by 5-MT1A receptor antagonists. Nonetheless, WAY 100635, unlike previous studies with pindolol, did not interfere with the effects of the antidepressant in the model. The ability of the combinat ion group to attenuate the hypothermic effects of 8-OH-DPAT faster than par oxetine alone, further emphasizes the role of the 5-HT1A receptor in the me chanism of action of antidepressants, and as a target for the development o f faster acting antidepressants. (C) 1999 Elsevier Science Inc.