EMD 281014 (0.001-0.05 mg/kg) or MA (0.1-5 mg/kg) blocked d-fenfluramine-induced HTR dose-dependently during ageing. The 5-HT1A antagonist WAY 100635 countered the inhibitory effect of MA on d-fenfluramine-induced HTR in 30-day old mice, whereas the adrenergic ɑ2 antagonist RS 79948 reversed MA\'s inhibitory effect in both 20- and 30- day old mice. d-Fenfluramine significantly increased c-fos expressions in PFC regions. MA (1 mg/kg) pretreatment significantly increased d-fenfluramine-evoked c-fos expression in different regions of PFC. EMD 281014 (0.05 mg/kg) failed to prevent d-fenfluramine-induced c-fos expression, but significantly increased it in one PFC region (PrL at - 2.68 mm).
EMD 281014 suppressed d-fenfluramine-induced HTR but failed to prevent d-fenfluramine-evoked c-fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c-fos. The suppressive effect of MA on d-fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT2A- and the inhibitory 5-HT1A- and ɑ2-receptors. MA-evoked increases in c-fos expression in PFC regions are due to the activation of diverse monoaminergic receptors through increased synaptic concentrations of 5-HT, NE and/or DA, which may also account for the additive effect of MA on d-fenfluramine-evoked changes in c-fos expression. Our findings suggest potential drug receptor functional interaction during development when used in combination.
结果:EMD281014(0.001-0.05mg/kg)或MA(0.1-5mg/kg)在衰老过程中剂量依赖性地阻断了d-芬氟拉明诱导的HTR。5-HT1A拮抗剂WAY100635抵消了MA对30日龄小鼠中d-芬氟拉明诱导的HTR的抑制作用,而肾上腺素能α2拮抗剂RS79948在20和30日龄小鼠中逆转了MA的抑制作用。d-芬氟拉明显著增加PFC区的c-fos表达。MA(1mg/kg)预处理显着增加了PFC不同区域的d-芬氟拉明诱发的c-fos表达。EMD281014(0.05mg/kg)未能阻止d-芬氟拉明诱导的c-fos表达,但在一个PFC区域(PrL为-2.68mm)中显着增加。
结论:EMD281014抑制d-芬氟拉明诱导的HTR,但未能阻止d-芬氟拉明诱发的c-fos表达,这表明在诱发c-fos的介导中涉及额外的5-羟色胺能受体。MA对d-芬氟拉明诱发的HTR的抑制作用是由于刺激性5-HT2A-和抑制性5-HT1A-和α2-受体之间公认的功能相互作用。在PFC区域中,MA引起的c-fos表达增加是由于通过增加5-HT的突触浓度激活了多种单胺能受体,NE和/或DA,这也可能解释了MA对d-芬氟拉明引起的c-fos表达变化的累加作用。我们的发现表明,当联合使用时,在开发过程中潜在的药物受体功能相互作用。