Influence of anxiolytic drugs on the effects of specific serotonin reuptake inhibitors in the forced swimming test in mice

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Abstract
This study aimed at investigating the effect of several selective serotonin reuptake inhibitors (SSRIs), given alone or in combination with anxiolytic drugs, on the time spent immobile in the forced swimming test in mice. The time spent immobile was dose-dependently reduced by acute administration of fluoxetine (4-64 mg/ kg, i.p.), paroxetine (1-32 mg/kg, s.c.) or sertraline (4-32 mg/kg, s.c.), indalpine was active at only one dose (16 mg/kg, i.p.), fluvoxamine (up to 16 mg/kg, i.p.) and citalopram (up to 4 mg/kg, i.p.) were inactive. The anti- immobility effect of fluoxetine (32 mg/kg) was antagonized by an acute co-administration of all anxiolytics tested, the GABAA/BZD receptor agonists, diazepam (2 mg/kg, i.p.), chlordiazepoxide (8 mg/kg, i.p.), lorazepam (0.125 mg/kg, i.p.), triazolam (0.06 mg/kg, i.p.) and alpidem (8 mg/kg, i.p.) and the 5-HT1A receptor partial agonist, buspirone (0.5 mg/kg, s.c.). The sedative neuroleptic, thioridazine (4 mg/kg, i.p.), was also found to counteract the effect of fluoxetine. Lorazepam, triazolam and buspirone also reversed the anti-immobility effect of paroxetine and sertraline, while diazepam and chlordiazepoxide did not. Alpidem reduced the effect of sertraline but not paroxetine, whereas the reverse was found with thioridazine. These data indicate that the influence of anxiolytics on the action of SSRI antidepressants is variable, depending on both the SSRI and the anxiolytic considered. The co-administration of the GABAA/BZD receptor antagonist, flumazenil (16 mg/kg, i.p.), with behaviourally inactive doses of fluoxetine, fluvoxamine and citalopram, resulted in a reduction of immobility The 5-HT1A receptor antagonist, (+)-WAY 100135 (8 mg/kg, s.c.), combined with a subactive dose of fluoxetine, but not with fluvoxamine, significantly reduced the time spent immobile. The 5-HT2A receptor antagonist, ketanserin (32 mg/kg, s.c.), which reduced immobility when given alone, did not interfere with fluoxetine given at a subactive dose. Although non-specific sedative and/or motor effects cannot be totally ruled out, these results suggest that pharmacodynamic interactions exist between various anxiolytics and SSRIs. These interactions probably involve both serotonergic and GABAergic processes.