COMBINING PINDOLOL AND PAROXETINE IN AN ANIMAL-MODEL OF CHRONIC ANTIDEPRESSANT ACTION - CAN EARLY-ONSET OF ACTION BE DETECTED

The realisation that pindolol may accelerate the effects of some antid epressant drugs in clinical trials has added extra impetus to the sear ch for faster acting antidepressants. Currently, no animal model of de pression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combin ing pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine ( 2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal mo del of chronic (but not acute) antidepressant activity. Ambulation sco res were measured in separate groups of rats, following 3, 7 and 14 da ys of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic res ponse to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tet ralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full re versal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbe ctomy-induced hyperactivity in the open field following 14 days of tre atment only, this being the normal time of an 'antidepressant' respons e in this model. However, the group treated with both paroxetine and p indolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates t hat the reversal of this aspect of the olfactory bulbectomy-induced be havioural syndrome is insensitive to the potential faster onset of ant idepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster f urther emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faste r acting antidepressants. However, an animal model sensitive to the ef fects of any such compound and the actions of pindolol remains elusive . (C) 1998 Elsevier Science B.V. All rights reserved.