Lithium produces bi-directionally regulation of mood disturbance, acts synergistically with anti-depressive/-manic agents, and did not deteriorate the cognitive impairment in murine model of bipolar disorder

Abstract

Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca²⁺ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca²⁺ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca²⁺ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.

Fig. 1. Comparison of brain Ca²+ activity, immobility time in the forced swim task (FST), and novel object preference in the novel object recognition (NOR) task among chronic unpredictable mild stress (CUMS) depression model groups.

A, B Brain Ca²⁺ activity; C immobility time in FST; D novel object preference in the NOR task. Representative in vivo two-photon imaging micrographs for each group are shown in (A). Li lithium, LTG lamotrigine, VPA valproate.

Fig. 2. Comparison of brain Ca²⁺ activity, exploratory behavior in the open field activity (OFA) task, and novel object preference in the novel object recognition (NOR) task among ketamine-induced mania (KM) model groups.

A, B Brain Ca²⁺ activity; C exploratory behavior in OFA task; D novel object preference in the NOR task. Representative in vivo two-photon imaging micrographs for each group are shown in (A). Li lithium, VPA valproate.

Fig. 3. Treatment effects in BP mice.

Brain Ca²⁺ activity revealed by in vivo two-photon imaging and behavior in BD mice (A). Depressive phase assessments of Ca²⁺ activity (B), forced swim task (FST) immobility time (C), and novel object recognition (NOR) behavior (D). Representative imaging micrographs for each group in the depressive phase are shown in (A). Manic phase assessments of Ca²⁺ activity (F), open field activity (OFA) pathlength (G), and NOR behavior (H). Representative imaging micrographs for each group in the manic phase are shown above the graphs (E). Li lithium, LTG lamotrigine, VPA valproate.