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

Abstract

Selective serotonin reuptake inhibitors (SSRIs) bind 5-HT transporters, leading to the accumulation of 5-HT and amelioration of depression. Although different mouse strains show varying sensitivity to SSRIs in mouse models of depression, the underlying mechanism of these strain differences remains unclear. Here, the SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2J mice but not C57BL/6J mice, whereas fluoxetine showed the opposite results. Paroxetine similarly reduced immobility time in both strains. The affinity of citalopram for the 5-HT transporter was 700-fold higher in DBA/2J mice than in C57BL/6J mice, whereas the affinity of fluoxetine was 100-fold higher in C57BL/6J mice than in DBA/2J mice. Furthermore, high citalopram concentrations were required for [3H]5-HT uptake in C57BL/6J but not in DBA/2J mouse cortical synaptosomes, whereas fluoxetine showed the opposite results. The effects of paroxetine on 5-HT transporter binding and synaptosomal 5-HT uptake were similar in the two strains. These results suggest that immobility duration depends on 5-HT transporter binding levels, which lead to apparent strain differences in immobility time in the FST and TST. Furthermore, differences in 5-HT transporter binding may cause variations in SSRI effects on behaviors.

Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs

“…Although further experiments are warranted to decipher the precise mechanisms by which the depletion of Cx43 produces positive effects on hippocampal 5‐HT tone specifically in response to fluoxetine, we then sought to determine to what extent these neurochemical changes in the hippocampus influenced the behavioural responses. As previously reported in C57BL/6 mice, we showed that a high dose of fluoxetine (ie 18 mg/kg) induced antidepressant‐like effects in the tail suspension test whereas a lower dose (5 mg/kg) failed to do so. One of the most remarkable results reported herein is that such a response was potentiated in Cx43 KD mice.…”

Chronic polypharmacy impairs explorative behavior and reduces synaptic functions in young adult mice

“…C57BL/6J is one of the most widely used mouse strains in preclinic pharmacology and toxicology studies [ 32 , 33 ]. The choice of the animal strain is of particular importance when performing drug investigations and previous studies have indeed reported as different strains respond more or less effectively to the same compound [ 34 , 35 ], depending on several variables like different pharmacodynamics and drug metabolism. For instance Jin ZL et al [ 34 ] found that some murine strains do not respond to citalopram to the same extent and in a dose-dependent way.…”

Developmental nicotine exposure precipitates multigenerational maternal transmission of nicotine preference and ADHD-like behavioral, rhythmometric, neuropharmacological, and epigenetic anomalies in adolescent mice

“…To isolate DA transporter (DAT)-mediated [ 3 H]-DA uptake, fluoxetine (200 nM) and desipramine (100 nM) were applied to block [ 3 H]-DA uptake via the serotonin transporter and norepinephrine transporter, respectively. Plate-loaded samples were incubated at 22 °C for 5 min (Jin et al, 2017). Nomifensine (500 μM) was used for blanks.…”