Background and Purpose : It has recently been suggested that 5-HT3 receptor blockade enhances selective serotonin reuptake inhibitor (SSRI) antidepressants efficacy and may reverse stress-induced deficits in rodents. Experimental Approach : To further explore this hypothesis, we used mice lacking the 5-HT3 receptor (Htr3a KO) and their wild-type (WT) controls to assess their response in behavioural paradigms relevant to anxiety and depression. Mice were studied under basal, antidepressant treatments and chronic social defeat stress (CSDS) conditions. Key Results : In basal conditions, Htr3a KO mice displayed anxiolytic- and antidepressant-like behaviours in the elevated plus maze, the social interaction and the forced swim (FST) tests, but behaved as WT mice in response to acute citalopram (2.5, 5.0 mg/kg) in the FST. However, the effects of fluoxetine (20 mg/kg) were blunted in Htr3a KO mice in these same tests. In an in vitro electrophysiological paradigm, a low dose citalopram treatment (5 mg/kg/day, 14 days) triggered 5-HT1AR desensitization only in the dorsal raphe nucleus of Htr3a KO, although a high dose (20 mg/kg/day, 14 days) desensitized 5-HT1A autoreceptor function equally in Htr3a KO and WT mice, suggesting that citalopram may become effective at lower doses when 5-HT3 receptors are inactivated. In addition, Htr3a deletion blocked CSDS-induced modification in the cortical expression of two genes involved in oxidative stress, CaMKIIa and SOD1. Conclusion and Implications : Taken together, these data show that Htr3a deletion promotes SSRI efficacy and prevents from stress-induced deleterious effects, suggesting that 5-HT3 receptor may represent an interesting target for the treatment of stress-related disorders.