Abstract
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 the prefrontal cortex (PFC), hippocampus and striatum. BDNF levels were measured in the hippocampus. 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 striatum, and increased BDNF levels in the hippocampus. The blockade of dopamine D1 and D2/D3 receptors inhibited leptin's antidepressant-like effects, whilst only the blockade of D1-like receptors blunted leptin-induced increments in prefrontal IL-1β levels. Our results indicate that leptin has antidepressant-like effects in an inflammatory model of depression with the contribution, at least partial, of dopamine receptors.
Highlights
Depression is the third leading source of years lived with disability worldwide and has a lifetime prevalence of 14.6% among people living in high-income countries [1, 2]
A recent metaanalysis evidenced that individuals with depression exhibit elevated peripheral levels interleukin (IL)-6, tumor necrosis factor (TNF)- α, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 compared to healthy controls [7]
Treatment resistant depression was accompanied by high inflammation (C-reactive protein >3 mg/l) in almost half of the patients enrolled in a previous study [8]
Summary
Depression is the third leading source of years lived with disability worldwide and has a lifetime prevalence of 14.6% among people living in high-income countries [1, 2]. In spite of the substantial burden associated with depression, only approximately a third of patients achieve remission after an adequate trial with first-line monoaminergic antidepressants [3]. Accumulating evidence indicates that peripheral immune activation and neuroinflammation may contribute to the development of depression [5, 6]. Treatment resistant depression was accompanied by high inflammation (C-reactive protein >3 mg/l) in almost half of the patients enrolled in a previous study [8]. Peripheral immune activation and inflammation may contribute to the emergence of depression through several mechanisms including the activation of the kynurenine pathway [10], alterations in neuronal plasticity [11], microglial activation [12], and neuroendocrine effects [13]
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