Strain differences in basal and post-citalopram extracellular 5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity
Strain differences in basal and post-citalopram extracellular 5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity
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DOI：
10.1111/j.1471-4159.2007.04806.x
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发表时间：
2007-11-01
影响因子：
4.7
通讯作者：
Invernizzi, R. W.
中科院分区：
文献类型：
--
作者：
Calcagno, E.;Canetta, A.;Invernizzi, R. W.
我们使用微透析技术比较基础的细胞外5-羟色胺（5-HT）和西酞普兰在不同品系的小鼠与功能不同的等位基因形式的色氨酸羟化酶-2（TPH-2），在脑5-HT合成的限速酶。与携带1473 C等位基因的C57 BL/6 J和C57 BL/6 N小鼠相比，携带TPH-2的1473 G等位基因的DBA/2 J、DBA/2N和BALB/c小鼠在内侧前额叶皮层和背侧海马（DH）中具有较少的透析液5-HT（减少20-40%）。细胞外5-HT的零净通量法估计证实了传统的微透析的结果。西酞普兰，1.25，5和20 mg/kg，剂量依赖性地增加细胞外5-HT在内侧前额叶皮质的C57 BL/6 J小鼠，最大效果在5 mg/kg，但有显着较小的效果在DBA/2 J和BALB/c小鼠和DBA/2 J小鼠的DH。色氨酸（TRP）负荷增强了DBA/2 J小鼠内侧前额叶皮质的基础细胞外5-HT，但不影响西酞普兰提高皮质和海马细胞外5-HT的能力。5-HT合成的损伤很可能解释了携带突变酶的小鼠中基础5-HT的减少和西酞普兰诱导的升高。这些发现可能解释了为什么DBA/2和BALB/c小鼠在强迫游泳试验中对西酞普兰没有反应。尽管TRP可能是改善西酞普兰抗抑郁作用的有用策略（切尔沃等人，2005），特别是在5-HT合成较低的受试者中，但多巴胺能和非多巴胺能机制对TRP作用的贡献仍有待阐明。
We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH-2 had less dialysate 5-HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20-40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5-HT estimated by the zero-net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose-dependently raised extracellular 5-HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5-HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram's ability to raise cortical and hippocampal extracellular 5-HT. The impairment of 5-HT synthesis quite likely accounts for the reduction of basal 5-HT and the citalopram-induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram (Cervo et al. 2005), particularly in subjects with low 5-HT synthesis, the contribution of serotonergic and non-serotonergic mechanisms to TRP's effect remains to be elucidated.