Long-term treatment with fluoxetine induces desensitization of 5-HT4 receptor-dependent signalling and functionality in rat brain
Long-term treatment with fluoxetine induces desensitization of 5-HT4 receptor-dependent signalling and functionality in rat brain
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DOI：
10.1111/j.1471-4159.2009.06210.x
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发表时间：
2009-08-01
影响因子：
4.7
通讯作者：
Castro, Elena
中科院分区：
文献类型：
--
作者：
Vidal, Rebeca;Valdizan, Elsa M.;Castro, Elena
抗抑郁药物的作用模式可能与单胺类受体的适应机制有关，包括5-HT4受体亚型。通过受体放射自显影、腺苷酸环化酶测定和细胞外记录技术，研究了选择性5-羟色胺再摄取抑制剂氟西汀重复治疗21天（5和10 mg/kg， p.o，每日1次）对大鼠脑5- ht4受体敏感性的影响。氟西汀在5-10 mg/kg剂量下降低了海马CA1区以及纹状体多个区域的5-HT4受体结合密度。以类似的方式，我们发现氟西汀10 mg/kg/天处理组对zacopride刺激的腺苷酸环化酶活性的反应明显较低。此外，在两种剂量的氟西汀处理的大鼠中，海马突触后5-HT4受体活性（以沙可匹利对CA1锥体细胞的兴奋作用来测量）被减弱。综上所述，这些结果支持了5-HT4受体信号通路在慢性选择性5-羟色胺再摄取抑制剂治疗后发生净减少的概念：这种效应可能是这些药物治疗效果的基础。
The mode of action of antidepressant drugs may be related to mechanisms of monoamines receptor adaptation, including serotonin 5-HT4 receptor subtypes. Here we investigated the effects of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine for 21 days (5 and 10 mg/kg, p.o., once daily) on the sensitivity of 5-HT4 receptors by using receptor autoradiography, adenylate cyclase assays and extracellular recording techniques in rat brain. Fluoxetine treatment decreased the density of 5-HT4 receptor binding in the CA1 field of hippocampus as well as in several areas of the striatum over the doses of 5-10 mg/kg. In a similar way, we found a significant lower response to zacopride-stimulated adenylate cyclase activity in the fluoxetine 10 mg/kg/day treated group. Furthermore, post-synaptic 5-HT4 receptor activity in hippocampus-measured as the excitatory action of zacopride in the pyramidal cells of CA1 evoked by Schaffer collateral stimulation was attenuated in rats treated with both doses of fluoxetine. Taken together, these results support the concept that a net decrease in the signalization pathway of 5-HT4 receptors occurs after chronic selective serotonin reuptake inhibitor treatment: this effect may underlie the therapeutic efficacy of these drugs.