BackgroundAccumulating evidence has indicated that S100B may be involved in the pathophysiology of depression. No published study has examined the effect of the antidepressant drug venlafaxine on S100B in animal models of depression. This study investigated S100B expression in the hippocampus and assessed the effect of venlafaxine on S100B mRNA level and protein expression in rats exposed to chronic unpredictable mild stress (CUMS).MethodsForty Sprague-Dawley rats were randomly divided into four groups as control, 0, 5 and 10 mg venlafaxine groups. The venlafaxine groups were exposed to CUMS from day 2 to day 43. Venlafaxine 0, 5 and 10 mg/kg were then administered from day 23 to day 43. We performed behavioral assessments with weight change, open-field and sucrose preference, and analyzed S100B protein expression and mRNA level in the hippocampus.ResultsThe CUMS led to a decrease in body weight, locomotor activity and sucrose consumption, but venlafaxine treatment (10 mg) reversed these CUMS-induced decreases Also, CUMS increased S100B protein expression and mRNA level in the hippocampus, but venlafaxine treatment (10 mg) significantly decreased S100B protein expression and mRNA level, which were significantly lower than the other treatment groups, without significant difference between the 10 mg venlafaxine and the control groups.ConclusionsOur findings showed that venlafaxine treatment (10 mg) may improve the depression-like behaviors and decrease over-expression of S100B protein and mRNA in the hippocampus in a rat model of depression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12993-016-0116-x) contains supplementary material, which is available to authorized users.