Antidepressant-like responses to lithium in genetically diverse mouse strains

Abstract

A mood stabilizing and antidepressant response to lithium is only found in a subgroup of patients with bipolar disorder and depression. Identifying strains of mice that manifest differential behavioral responses to lithium may assist in the identification of genomic and other biologic factors that play a role in lithium responsiveness. Mouse strains were tested in the forced swim test (FST), tail suspension test (TST) and open-field test after acute and chronic systemic and intracerebroventricular (ICV) lithium treatments. Serum and brain lithium levels were measured. Three (129S6/SvEvTac, C3H/HeNHsd and C57BL/6J) of the eight inbred strains tested, and one (CD-1) of the three outbred strains, showed an antidepressant-like response in the FST following acute systemic administration of lithium. The three responsive inbred strains, as well as the DBA/2J strain, displayed antidepressant-like responses to lithium in the FST after chronic administration of lithium. However, in the TST, acute lithium resulted in an antidepressant-like effect only in C3H/HeNHsd mice. Only C57BL/6J and DBA/2J showed an antidepressant-like response to lithium in the TST after chronic administration. ICV lithium administration resulted in a similar response profile in BALB/cJ (non-responsive) and C57BL/6J (responsive) strains. Serum and brain lithium concentrations showed that behavioral results were not because of differential pharmacokinetics of lithium in individual strains, suggesting that genetic factors likely regulate these behavioral responses to lithium. Our results indicate that antidepressant-like responses to lithium in tests of antidepressant efficacy varies among genetically diverse mouse strains. These results will assist in identifying genomic factors associated with lithium responsiveness and the mechanisms of lithium action.

Figure 1. Time course of changes in lithium concentrations in serum and brain after a single i.p. injection of 200mg/kg lithium in C57BL/6J mice

Data are expressed as mean ± SEM. n:6 animals per time point.

Figure 2. Immobility time in the forced swim test five hours after a single injection of saline, 200, 300, or 400 mg/kg lithium

*:p<0.05, **:p<0.01, ***:p<0.001 denote a significant difference compared to saline group, Dunnett’s post hoc test. Data are expressed as mean ± SEM. n:6–8 animals per group for each strain.

Figure 3. Immobility time in the tail suspension test five hours after a single injection of saline, 200, 300, or 400 mg/kg lithium

**:p<0.01 denotes a significant difference compared to saline group, Dunnett’s post hoc test. Data are expressed as mean ± SEM. n:7–9 animals per group for each strain.

Figure 4. Immobility time in the tail suspension test after three weeks of chronic lithium administration

**:p<0.01, ***:p<0.001 denote a significant, unpaired t-test. Data are expressed as mean ± SEM. n:10–12 animals per group for each strain.

Figure 5. Immobility time in the forced swim test after 3 weeks of chronic lithium administration

*:p<0.05, **:p<0.01, ***:p<0.001 denote a significant difference; unpaired t-test. Data are expressed as mean ± SEM. n:10–12 animals per group for each strain.

Figure 6. Immobility time in forced swim test 30 minutes after ICV administration of 3 μl, 600 mmol/L LiCl into the right lateral ventricle

*:p<0.05 denotes a significant difference, unpaired t-test. Data are expressed as mean ± SEM. n:5–8 animals per group for each strain.