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Aim To characterize the SSRIs sensitivity in C57 and DBA mouse strain and identify the protein structural determinants that contribute to the SSRIs sensitivity.Methods Multiple behavioral assays were conducted to characterize the SSRIs sensitivity in C57 and DBA mouse strain.We performed in vitro binding and uptake assays to assess the pharmacological properties differences of the SSRIs in C57 and DBA mouse strain.Results The major difference between the 5HT transport kinetics of the SERTs was found in their maximal transport capacity rather than the transporter s apparent affinity for 5HT in two mouse strains.C57 mice displayed a significant loss in citalopram sensitivity.DBA mice displayed a significant loss in fluoxetine sensitivity.Paroxetine and YL0919 displayed the same sensitivity in tow mouse strain.Conclusion Results suggest that the two mouse strain have different responses activity to the treatment of SSRIs.The Kd values for 5HT transporter binding were significantly different among the five compounds of SSRIs we studied in C57 and DBA mouse strain as well as reuptake assays.