Mouse strain differences in SSRI sensitivity correlates with serotonin transporter binding and function

Abstract

OBJECTIVESelective serotonin reuptake inhibitors (SSRIs) bind 5‐HT transporters, leading to the accumulation of 5‐HT and amelioration of depression. Although different mouse strain showed different sensitivity to SSRIs in mouse models of depression, the reason for these strain differences remains unclear. Here, Therefore, in the present study, we examined immobility time and loco‐motor activity in two mouse strains, namely, C57BL/6J and DBA/2J mice, and the effects of the SSRIs fluoxetine. Furthermore, we analyzed 5‐HT transporter binding and reuptake inhibition in both strains to explore their relationship with the immobility and locomotor activity effects of the three SSRIs in these two mouse strains.METHODSStrain differences in SSRI effects in the tail suspension test and forced swimming test. To initiate our studies, we sought to confirm that SERT strain variation did not alter SERT protein expression, 5‐HT recognition, or uptake activity when expressed in C57BL/6J and DBA/2J mice. Radioligand binding assays were conducted to determine the affinity of the SSRIs for the 5‐HT transporters in the two mouse strains.RESULTSWe found that the SSRI citalopram dose dependently reduced immobility time in both the FST and TST in DBA/2J but not C57BL/6J mouse strains, whereas fluoxetine showed opposite results. Paroxetine reduced immobility time similarly in both strains. The affinity of citalopram for the 5‐HT transporter in DBA/2J mice was 700‐fold higher than that for in C57BL/6J mice, whereas the affinity of fluoxetine in C57BL/6J mice was 100‐fold higher than that in the DBA/2J mouse. Furthermore, High citalopram concentrations were required to [3H]5‐HT uptake in C57BL/6J but not DBA/2J mouse cortical synaptosomes, whereas fluoxetine also showed opposite results.CONCLUSIONThese results suggest that immobility duration depends on 5‐HT transporter binding levels, leading to apparent strain differences in immobility time in the FST and TST. Furthermore, differences in 5‐HT transporter binding may cause variations in SSRI responses on behaviors. SERT mutation mice maintained sensitivity to paroxetine, an antidepressant that is unaffected by the mouse mutation. Therefore, the background strain of these mice likely contributes to the acute behavioral actions of SSRIs in immobility time. Future studies should investigate additional neural substrates and molecular mechanisms underlying strain variations in mouse models of depression to help identify genetic predispositions to this disorder in humans.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (No. 81773708 and 81703484), Support Project of High‐level Teachers in Beijing Municipal Universities in the Period of 13th Five–year Plan (grant number CIT&ICD201704095) and the Scientific Research Common Program of Beijing Municipal Commission of Education (grant number KM201710025003).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.