López-Zapata Antonio, León-Navarro David Agustín, Crespo María, Albasanz José Luis, Martín Mairena
Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias y Tecnologías Químicas/Facultad de Medicina de Ciudad Real, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain.
Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias y Tecnologías Químicas/Facultad de Medicina de Ciudad Real, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain.
Neuroscience. 2017 Mar 6;344:187-203. doi: 10.1016/j.neuroscience.2016.12.019. Epub 2016 Dec 22.
Antidepressant and anxiolytic drugs are widely consumed even by pregnant and lactating women. The metabotropic glutamate receptor 5 (mGlu) antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) exerts antidepressant- and anxiolytic-like actions. Given that treatment for anxiety and depression use to be prolonged in time, it is conceivable a possible modulation of metabotropic glutamate receptors (mGlu receptors) after prolonged MPEP exposure, which could also modify adenosine A receptors (AR) since functional cross-talk between them has been reported. Here we report that MPEP crosses placental barrier and reaches neonatal brain through maternal milk using LC-MS/MS methods. Therefore, we analyzed mGlu receptors, mainly mGlu, and AR in both maternal and fetal brain after chronic maternal consumption of MPEP during gestation and/or lactation using radioligand binding, Western-blotting, real-time PCR and phospholipase C (PLC) activity assays. In maternal brain, chronic MPEP consumption caused a significant loss of mGlu, including mGlu, and AR receptors level in plasma membrane. PLC activity assays showed that mGlu signaling pathway was desensitized. No variations on mRNA level coding AR, AR and mGlu were found after MPEP treatments. In female neonatal brain, maternal consumption of MPEP caused a significant increase in mGlu, including mGlu, and AR receptors level. Neither mGlu receptors nor AR were modified in male neonatal brain after maternal MPEP intake. Finally, neither molecular nor behavioral changes (anxiety- and depression-like behavior) were observed in 3-month-old female offspring. In summary, mGlu and AR are altered in both maternal and female neonatal brain after chronic maternal consumption of MPEP during gestation and/or lactation.
抗抑郁药和抗焦虑药甚至被孕妇和哺乳期妇女广泛使用。代谢型谷氨酸受体5（mGlu）拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）具有抗抑郁和抗焦虑样作用。鉴于焦虑和抑郁的治疗通常需要较长时间，长期接触MPEP后，代谢型谷氨酸受体（mGlu受体）可能会受到调节，这也可能会改变腺苷A受体（AR），因为它们之间已报道存在功能性相互作用。在此，我们报告使用液相色谱-串联质谱法（LC-MS/MS）发现MPEP可穿过胎盘屏障并通过母乳进入新生儿大脑。因此，我们使用放射性配体结合、蛋白质免疫印迹、实时聚合酶链反应（PCR）和磷脂酶C（PLC）活性测定法，分析了孕期和/或哺乳期母体长期摄入MPEP后母体和胎儿大脑中的mGlu受体，主要是mGlu，以及AR。在母体大脑中，长期摄入MPEP导致质膜上mGlu，包括mGlu和AR受体水平显著降低。PLC活性测定表明mGlu信号通路脱敏。MPEP处理后，编码AR、AR和mGlu的mRNA水平未发现变化。在雌性新生鼠大脑中，母体摄入MPEP导致mGlu，包括mGlu和AR受体水平显著升高。母体摄入MPEP后，雄性新生鼠大脑中的mGlu受体和AR均未改变。最后，在3个月大的雌性后代中未观察到分子或行为变化（焦虑和抑郁样行为）。总之，孕期和/或哺乳期母体长期摄入MPEP后，母体和雌性新生鼠大脑中的mGlu和AR均发生改变。
