Diniz Cassiano R A F, Rodrigues Murilo, Casarotto Plínio C, Pereira Vítor S, Crestani Carlos C, Joca Sâmia R L
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
Brain Res. 2017 Dec 1;1676:19-27. doi: 10.1016/j.brainres.2017.09.011. Epub 2017 Sep 12.
Depression is a common mental disorder that affects millions of individuals worldwide. Available monoaminergic antidepressants are far from ideal since they show delayed onset of action and are ineffective in approximately 40% of patients, thus indicating the need of new and more effective drugs. ATP signaling through P2 receptors seems to play an important role in neuropathological mechanisms involved in depression, since their pharmacological or genetic inactivation induce antidepressant-like effects in the forced swimming test (FST). However, the mechanisms involved in these effects are not completely understood. The present work investigated monoamine involvement in the antidepressant-like effect induced by non-specific P2 receptor antagonist (PPADS) administration. First, the effects of combining sub-effective doses of PPADS with sub-effective doses of fluoxetine (FLX, selective serotonin reuptake inhibitor) or reboxetine (RBX, selective noradrenaline reuptake inhibitor) were investigated in mice submitted to FST. Significant antidepressant-like effect was observed when subeffective doses of PPADS was combined with subeffective doses of either FLX or RBX, with no significant locomotor changes. Next, the effects of depleting serotonin and noradrenaline levels, by means of PCPA (p-Chlorophenylalanine) or DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) pretreatment, respectively, was investigated. Both, PCPA and DSP-4 pretreatment partially attenuated PPADS-induced effects in FST, without inducing relevant locomotor changes. Our results suggest that the antidepressant-like effect of PPADS involves modulation of serotonin and noradrenaline levels in the brain.
抑郁症是一种常见的精神障碍，影响着全球数百万人。现有的单胺能抗抑郁药远非理想之选，因为它们起效延迟，且在约40%的患者中无效，因此表明需要新的、更有效的药物。通过P2受体的ATP信号传导似乎在抑郁症相关的神经病理机制中起重要作用，因为其药理学或基因失活在强迫游泳试验（FST）中诱导出抗抑郁样效应。然而，这些效应所涉及的机制尚未完全明确。本研究调查了单胺在非特异性P2受体拮抗剂（PPADS）给药诱导的抗抑郁样效应中的作用。首先，在接受FST的小鼠中研究了将亚有效剂量的PPADS与亚有效剂量的氟西汀（FLX，选择性5-羟色胺再摄取抑制剂）或瑞波西汀（RBX，选择性去甲肾上腺素再摄取抑制剂）联合使用的效果。当亚有效剂量的PPADS与亚有效剂量 的FLX或RBX联合使用时，观察到显著的抗抑郁样效应，且无明显的运动变化。接下来，分别通过PCPA（对氯苯丙氨酸）或DSP-4（N-（2-氯乙基）-N-乙基-2-溴苄胺盐酸盐）预处理来降低5-羟色胺和去甲肾上腺素水平，并研究其效果。PCPA和DSP-4预处理均部分减弱了PPADS在FST中诱导的效应，且未引起相关运动变化。我们的结果表明，PPADS的抗抑郁样效应涉及对大脑中5-羟色胺和去甲肾上腺素水平的调节。
