Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test

Abstract

Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to investigate further the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg⁻¹, IP) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg⁻¹, IP; P < 0.01), paroxetine (4 mg kg⁻¹, IP; P < 0.01), citalopram (4 mg kg⁻¹, IP; P < 0.01) and sertraline (2 mg kg⁻¹, IP; P < 0.01) in the forced swimming test. However, pretreatment with buspirone did not induce antidepressant-like effects when tested in combination with fluoxetine (4 mg kg⁻¹, IP). Each antidepressant tested reduced immobility time in the forced swimming test [citalopram (16 mg kg⁻¹, IP; P < 0.01), fluoxetine (32 mg kg⁻¹, IP; P < 0.01), fluvoxamine (32 mg kg⁻¹, IP; P < 0.01), paroxetine (16 mg kg⁻¹, IP; P < 0.01) and sertraline (16 mg kg⁻¹, IP; P < 0.01)]. Pretreatment with buspirone (0.5 mg kg⁻¹, IP), or its major metabolite 1-PP (0.5 mg kg⁻¹, IP), attenuated all SSRI-induced anti-immobility effects (P < 0.01). Concomitant studies of locomotor activity ruled out any stimulant or sedative effects of the interactions. The results of the present study suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-HT_1A receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (1-PP) acting at alpha₂-adrenoreceptors.