Low-dose lithium mono- and adjunctive therapies improve MK-801-induced cognitive impairment and schizophrenia-like behavior in mice - Evidence from altered prefrontal lobe Ca2+ activity

Abstract

Background: Few studies have evaluated lithium either as monotherapy or in combination with anti-psychotic agents to improve cognition in murine models of schizophrenia.

Methods: Visualization of Ca²⁺ activity in the prefrontal cortex was used to characterize brain neural activity. Novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FCT) tests were used to characterize cognitive performance; while pre-pulse inhibition (PPI), elevated plus maze (EPM) and the open field test (OFT) were used to characterize schizophrenia-like behavior.

Results: A 28-day course of low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) improved Ca²⁺ ratio by 70.10 %, PPI by 69.28 %, NOR by 70.09 %, MWM by 71.28 %, FCT by 68.56 %, EPM by 70.95 % and OFT by 75.23 % compared to the results of positive controls. Unexpectedly, moderate-dose lithium (human equivalent dose of 500 mg/day) used either as monotherapy or as an adjunct with quetiapine worsened Ca²⁺ activity, PPI, MWM, FCT, EPM, and OPT.

Limitations: Our study cannot explain the contrasting positive and negative effects of low-dose and moderate-dose lithium, respectively, when used either as monotherapies or as adjuncts. Further studies, especially Western blotting, may reveal molecular mechanisms of action.

Conclusions: Low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) provided the best improvements. Furthermore, benefits persisted for 14 days post-treatment. Our data provide directions for further research of therapeutic alternatives to mitigate schizophrenia-related cognopathy.

Keywords: Cognition; Lithium; Quetiapine; Schizophrenia; Schizophrenia-like behavior.