Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr2B-/-), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr2B-/- mice. We find, here, that Htr2B-/- mice display an antidepressant-like phenotype, which includes reduced latency to feed in the Novelty Suppressed Feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr2B+/+) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr2B-/- mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr2B-/- mice and, similarly, no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model, displaying panoply of conditions among which, behavioral, neurotrophic and plastic causative factors can be analyzed.