Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression

The Limitations of antidepressant drugs to treat depression has warranted o ngoing research to identify pharmacological agents and strategies which off er a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of actio n of antidepressants and the recent development of selective reuptake inhib itors of these transmitters has provided the opportunity to determine the e ffects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline re uptake, sertraline, a selective serotonin reuptake inhibitor and a combinat ion treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine ( 2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobi lity time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the 'open -field' test. Examination of the onset of the antidepressant effect in the 'open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg /kg) and the combination reduced the behavioural hyperactivity after 14 day s but not before this following 3, 7 or 10 days of treatment. Reduced 5-hyd roxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydrox ytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-( di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 m g/kg s.c.) occurred in the reboxetine and sertraline combination treated gr oups following both 7 and 14 days administration indicating changes to 5-HT 1A receptor and alpha(2)-adrenoceptor sensitivity. The results indicate tha t changes to 8-OH-DPAT and clonidine-induced responses occur quicker with t he combination treatment than with either reboxetine or sertraline treatmen ts alone. (C) 1999 Elsevier Science B.V. All rights reserved.