Abstract
BACKGROUND: Lithium is a mood stabilizer with both antidepressant and antimanic properties, however 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: This study aimed to assess the roles of both genetic and non-genetic factors such as sex and non-shared environmental conditions that may mediate differential behavioral responses to lithium. METHODS: Mice were treated with lithium for 10 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 response to 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.