Cordeiro Rafaela Carneiro, Chaves Filho Adriano José Maia, Gomes Nayana Soares, Tomaz Viviane de Sousa, Medeiros Camila Dantas, Queiroz Ana Isabelle de Góis, Maes Michael, Macedo Danielle S, Carvalho Andre F
Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Universidade Federal do Ceará Fortaleza, Brazil.
McGill Group for Suicide Studies, Douglas Mental Health Institute, McGill University Montreal, QC, Canada.
Front Psychiatry. 2019 Mar 12;10:125. doi: 10.3389/fpsyt.2019.00125. eCollection 2019.
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.
抑郁症是一种慢性复发性疾病，与高发病率和自杀风险相关。瘦素最初被描述为一种抗肥胖激素，但已有报道称其在中枢神经系统中有多种作用。事实上，瘦素调节中脑边缘区域的多巴胺能神经传递，并在基于应激的模型中具有类似抗抑郁的特性。在本研究中，我们首次研究了瘦素在脂多糖（LPS）诱导的抑郁样行为动物模型中的假定抗抑郁样作用，以及多巴胺受体作为这些行为效应介质的潜在参与情况。在给予LPS之前，给小鼠注射瘦素（1.5mg/kg，腹腔注射）或丙咪嗪。为了评估多巴胺受体的参与情况，在注射瘦素之前，不同的实验组分别用多巴胺能拮抗剂SCH23390（针对D1受体）或雷氯必利（针对D2/D3受体）进行预处理。LPS注射后24小时，将小鼠进行强迫游泳和蔗糖偏好测试。此外，还测定了前额叶皮质（PFC）、海马体和纹状体中的IL-1β水平。测量了海马体中的脑源性神经营养因子（BDNF）水平。我们的结果表明，与丙咪嗪类似，瘦素可预防LPS诱导的核心行为改变（绝望样行为和快感缺失），而不改变运动能力。在神经化学分析中，瘦素恢复了LPS诱导的PFC和纹状体中IL-1β水平的变化，并增加了海马体中的BDNF水平。多巴胺D1和D2/D3受体的阻断抑制了瘦素的抗抑郁样作用，而只有D1样受体的阻断减弱了瘦素诱导的前额叶IL-1β水平的升高。我们的结果表明，瘦素在抑郁症的炎症模型中具有抗抑郁样作用，至少部分是由多巴胺受体介导的。
