Leptin prevents lipopolysaccharide-induced depressive-like behaviors in mice: involvement of dopamine receptors

Depression is a chronic and recurrent disorder, associated with high morbidity and risk of suicide. Leptin was firstly described as an anti-obesity hormone, but several actions of leptin in CNS have been reported. In fact, leptin regulates dopaminergic neurotransmission in mesolimbic areas and has antidepressant-like properties in stress-based models. In the present study, we investigated, for the first time, putative antidepressant-like effects of leptin in an animal model of depressive-like behaviors induced by lipopolysaccharide (LPS), and the potential involvement of dopamine receptors as mediators of those behavioral effects. Mice were injected leptin (1.5 mg/kg, ip.) or imipramine prior to LPS administration. To evaluate the involvement of dopamine receptors, different experimental groups were pretreated with either the dopaminergic antagonist SCH23390, for D1 receptors or raclopride, for D2/D3 receptors, prior to leptin injection. Twenty-four hours post-LPS, mice were submitted to the forced swimming and sucrose preference tests. In addition, IL-1β levels were determined in prefrontal cortex (PFC), hippocampus (HC) and striatum (ST), while BDNF levels were measured in the HC. Our results showed that leptin, similarly to imipramine, prevented the core behavioral alterations induced by LPS (despair-like behavior and anhedonia), without altering locomotion. In neurochemical analysis, leptin restored LPS-induced changes in IL-1β levels in the PFC and ST, and increased BDNF levels in HC. The blockade of dopamine D1 as well as D2/D3 receptors inhibited leptin’s antidepressant-like effects, whilst only blockade of D1-like receptors blunted leptin-induced increments in IL-1β levels in the PFC. This work indicates that leptin has antidepressant-like effects in an inflammatory model of depression and that dopaminergic effects may contribute to those effects.