The effect of lithium on behavioral functions in adolescent rats exposed to chronic unpredictable mild stress with respect to brain-derived neurotrophic factor and glycogen synthase kinase-3 beta levels in the prefrontal cortex

Chronic unpredictable mild stress (CUMS) is widely used as a reliable method to induce depressive states and anhedonia in rodents. Lithium is one of the well-known drugs used for the alleviation of symptoms in different neuropsychiatric disorders such as depression and bipolar disorder. In this research, we evaluated the efficacy of several doses of lithium on behavioral changes induced by CUMS. Also, the expression level of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase-3 beta (GSK-3beta) in the prefrontal cortex was evaluated. CUMS was done using various unpredictable stressors for 14 days. Lithium was injected at the doses of 10, 30, and 50 mg/kg. Locomotor activity, anxiety-like behavior, pain perception, and depressive-like behavior were assessed using the open field test, the novelty-suppressed feeding test, the hot plate test, and the forced swim test, respectively. The results revealed that CUMS decreased locomotor activity, increased anxiety- and depressive-like behaviors, increased pain threshold, decreased climbing, decreased BDNF level, and increased GSK-3beta level in the prefrontal cortex. However, lithium dose-dependently restored all these effects. In control rats, lithium (50 mg/kg) decreased locomotion and GSK-3beta expression levels. In conclusion, the results suggested that deleterious effects of CUMS may be mediated via BDNF and GSK-3beta in the prefrontal cortex, and lithium via suppressing GSK-3beta and upregulating BDNF expression levels in the prefrontal cortex can restore CUMS effects.