Abstract：
The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT2A receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT2A receptor agonists such as ( ±)- 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT2A antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC. Moreover, the nonselective monoamine releaser methamphetamine (MA) suppressed DOI-induced HTR through ageing via concomitant activation of inhibitory 5-HT1A receptors, but enhanced DOI-evoked c-fos expression. d-Fenfluramine is a selective 5-HT releaser and induces HTR in mice, whereas MA does not. Currently, we investigated whether EMD 281014 or MA would alter: (1) d-fenfluramine-induced HTR frequency in 20-, 30- and 60-day old mice, (2) d-fenfluramine-evoked c-fos expression in PFC, and (3) whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors would prevent suppressive effect of MA on d-fenfluramine-induced HTR.
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.
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.
摘要：
背景：小鼠的头部抽搐反应（HTR）被认为是致幻剂和5-羟色胺5-HT2A受体功能的行为模型，以及人类的Tourette综合征。它由5-HT2A受体激动剂如前额叶皮质(PFC)中的(±)-2,5-二甲氧基-4-碘苯丙胺(DOI)介导。5-HT2A拮抗剂EMD281014可以防止老化过程中DOI诱导的HTR和PFC不同区域的c-fos表达。此外，非选择性单胺释放剂甲基苯丙胺（MA）通过伴随的抑制性5-HT1A受体的激活，通过衰老抑制DOI诱导的HTR，但增强了DOI诱发的c-fos表达。d-芬氟拉明是一种选择性5-HT释放剂，在小鼠中诱导HTR，而MA没有。目前,我们调查了EMD281014或MA是否会改变：（1）d-芬氟拉明诱导的HTR频率在20-，30和60天大的老鼠，(2)d-芬氟拉明诱发的c-fos在PFC中的表达,(3)阻断抑制性5-羟色胺能5-HT1A-或肾上腺素能α2-受体是否会阻止MA对d-芬氟拉明诱导的HTR的抑制作用。
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。
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。
