Chronic lithium decreases Nurr1 expression in the rat brain and impairs spatial discrimination.

Lithium (Li+) is a drug used for the treatment of neuropsychiatric disorders, whereas Nuclear receptor-related factor 1 (Nurr1) has been implicated in normal and aberrant cognitive processes. Li+'s effects on cognition and Nurr1 expression were examined. Rats were exposed to Li+ in their diet for 4 weeks and only those reaching Li+ blood concentrations within the established clinically therapeutic range were used. Li+ decreased rearing activity in rats, but did not affect horizontal locomotion nor object recognition memory. In contrast, Li+ treated animals were significantly impaired in the initial, but not late, stages of acquisition of a hippocampal-dependent spatial discrimination task. In agreement with the behavioral results, chronic Li+ caused a significant downregulation of basal Nurr1 expression in several brain regions. In particular, a significant negative correlation between Li+ blood levels and Nurr1 expression was identified in the CA1 hippocampal subregion, but not in CA3, perirhinal cortex or the dorsal endopiriform nucleus. Upregulation of hippocampal Nurr1 levels to those of controls were observed in Li+ treated rats following training in the spatial task. Overall, the results suggest that the effects of Li+ on the brain may be particularly relevant to hippocampal-dependent cognitive processes involving Nurr1 expression.