Differential antidepressant-like response to lithium treatment between mouse strains: effects of sex, maternal care, and mixed genetic background

Abstract

Background Lithium is a mood stabilizer with both antidepressant and antimanic properties, though its mechanism of action is unclear. Identifying the genetic factors that influence lithium's therapeutic actions will be an important step to assist in identifying such mechanisms. We previously reported that lithium treatment of male mice has antidepressant-like effects in the C57BL/6J strain but that such effects were absent in the BALB/cJ strain. Objectives To assess the roles of both genetic, and non-genetic factors such as sex and non-shared environmental factors that may mediate differential behavioral responses to lithium. Methods Mice were treated with lithium for ten days and then tested in the forced swim test followed by lithium discontinuation and retesting to assess effects of lithium withdrawal. We also assessed effects of sex and cross-fostering on lithium response between the C57BL/6J and BALB/cJ strains, and antidepressant-like effects of lithium in the hybrid CB6F1/J strain that is derived from C57BL/6J and BALB/cJ parental strains. Results Neither sex nor maternal care significantly influenced the differential antidepressant-like profile of lithium. Withdrawal from lithium treatment reversed antidepressant-like effects in the C57BL/6J strain, but had no effects in BALB/cJ mice. Lithium treatment did not result in antidepressant-like effects in the CB6F1/J strain. Conclusions Genetic factors are likely primarily responsible for differential antidepressant-like effects of lithium in the C57BL/6J and BALB/cJ strains. Future studies identifying such genetic factors may help to elucidate the neurobiological mechanisms of lithium's therapeutic actions.

PDE11A negatively regulates lithium responsivity

“…This is consistent with the fact that the C57BL/6J and 129S6/SvEvTac mice with low PDE11A4 expression are more sensitive to the effects of lithium in TST and forced swim test (FST) than BALB/cJ mice with high PDE11A4 expression (Figure 1-2, S1-S3)[45, 50]. Specifically, following 3 weeks of lithium treatment, C57BL/6J mice demonstrated a significant antidepressant-like effect in both TST and FST, 129S6/SvEvTac mice demonstrated a significant antidepressant-like effect only in FST, and BALB/cJ mice demonstrated no effect in either assay [45].…”

Chronic Stress May Not Be a Factor in the Behavioral Response to Chronic Lithium in ICR Mice

“…The effect of Li in the FST was in agreement with previous work (e.g., [13,14]), but the lack of effects in females was against expectations. Previous studies did not find sex differences in the effects of lithium in the FST in C57BL/6J mice [30,31] or black Swiss mice [32], but we did not find any previous comparison in ICR mice and this issue should be further examined separately. The effects of Li to reduce SSP in the males (Fig.…”

Molecular actions and clinical pharmacogenetics of lithium therapy

“…Inbred mice strains that have a lower functioning variant of Tph2 gene (e.g., BALB/cJ) manifest a reduced response to SSRI treatment as assessed in the forced swim test compared to carriers of the normal functioning variant of Tph2 (e.g., C57BL/6J) (Cervo et al, 2005; Calcagno et al, 2007; Guzzetti et al, 2008). The same profile of treatment response in different inbred mouse strains was also shown in response to lithium treatment (Can et al, 2011, 2013). …”

“…Lithium is also effective in reducing depression-like behaviors in animal models as measured in behavioral tests such as the forced swim test and tail suspension test (O’Brien et al, 2004; Bersudsky et al, 2007; Gould et al, 2008; Can et al, 2011; Can et al, 2013). There is now extensive evidence suggesting that lithium’s action to reduce depression-like behaviors seems to be related to effects on GSK-3 (Gould et al, 2004b; Gould et al, 2007; Omata et al, 2011; Zhang et al, 2012).…”