5-HT 1A receptor antagonists neither potentiate nor inhibit the effects of fluoxetine and befloxatone in the forced swim test in rats

Abstract

Recent clinical data suggest that coadministration of pindolol with an antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor fluoxetine, can shorten the time to onset of clinical activity and increase the proportion of responders. We have examined the interaction of antidepressants with 5-HT 1A receptors using the forced swim test in rats using both (±)-pindolol and the selective 5-HT 1A receptor antagonist WAY 100,635 ( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(pyridinyl) cyclohexanecarboxamide trihydrochloride) in combination with either fluoxetine or the selective monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.125–1 mg/kg s.c.), used as a reference for 5-HT 1A agonist activity, reduced immobility in the forced swim test and this effect was significantly antagonised by WAY 100,635. WAY 100,635 alone (0.01–0.1 mg/kg s.c.) was without effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to increase immobility. In contrast, (±)-pindolol (1–16 mg/kg s.c.) significantly reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the antidepressants fluoxetine (10–80 mg/kg p.o.) and befloxatone (0.03–1 mg/kg p.o.) dose-dependently reduced immobility time. When the antidepressants were combined with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively high doses, significantly reduced their activity in this test. Combination of the antidepressants with (±)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a significant interaction. These results demonstrate that the anti-immobility effects of fluoxetine and befloxatone are neither facilitated nor antagonised by doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT. Furthermore, there was no evidence that coadministration of the antidepressants with (±)-pindolol was able to facilitate their antidepressant-like effects. Thus, whereas direct agonist activity at 5-HT 1A receptors can modulate immobility in the forced swim test, this receptor subtype does not appear to play a major role in the antidepressant-like effects of fluoxetine or befloxatone under the conditions used in this study.