Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression
Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression
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DOI：
10.1523/jneurosci.1816-05.2005
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发表时间：
2005-09-07
影响因子：
5.3
通讯作者：
Invernizzi, RW
中科院分区：
文献类型：
--
作者：
Cervo, L;Canetta, A;Invernizzi, RW
DBA/2J和BALB/c小鼠合成5-羟色胺(5-HT)的限速酶色氨酸羟化酶的多态性与DBA/2J和BALB/c比C57BL/6J和129/Sv小鼠合成的5-羟色胺少有关。我们选择了强迫游泳实验，一种用于评估药物抗抑郁潜力的小鼠模型，以及神经化学技术来研究菌株对选择性5-羟色胺再摄取抑制剂西酞普兰的反应差异。西酞普兰可缩短C57BL/6J和129/Sv小鼠的不动时间，但对DBA/2J和BALB/c小鼠无此作用。该药减少了C57BL/6J和129/Sv小鼠体内5-羟色氨酸(5-HTP)的积累，但对DBA/2J和BALB/c小鼠的影响要小得多。色氨酸可促进DBA/2J和BALB/c小鼠体内5-HTP的蓄积，恢复西酞普兰的抗抑郁样作用，而对C57BL/6J和129/Sv小鼠体内5-羟色胺合成的药理抑制作用可阻断其抗抑郁作用。由于在行为测试结束时，在儿茶酚胺合成、运动活动和脑内西酞普兰水平方面没有品系差异，结果表明，西酞普兰未能减少DBA/2J和BALB/c小鼠的不动时间是由于5-羟色胺合成的基因依赖性障碍。菌株间比较可能是了解选择性5-羟色胺再摄取抑制剂反应潜在机制的有用策略。
Polymorphism of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of brain serotonin (5-HT), is associated with less synthesis of brain 5-HT in DBA/2J and BALB/c than in C57BL/6J and 129/Sv mice. We selected the forced swimming test, a mouse model used to assess the antidepressant potential of drugs, and neurochemical techniques to study strain differences in the response to citalopram, a selective 5-HT reuptake inhibitor. Citalopram reduced immobility time in C57BL/6J and 129/Sv mice but had no such effect in DBA/2J and BALB/c mice. The drug reduced accumulation of 5-hydroxytryptophan (5-HTP), an indicator of 5-HT synthesis, in C57BL/6J and 129/Sv mice but much less in DBA/2J and BALB/c mice. Pretreatment with tryptophan raised 5-HTP accumulation and reinstated the antidepressant-like effect of citalopram in DBA/2J and BALB/c mice, whereas pharmacological inhibition of 5-HT synthesis prevented the effect of citalopram in C57BL/6J and 129/Sv mice. Because there were no strain differences in catecholamine synthesis, locomotor activity, and brain levels of citalopram at the end of the behavioral test, the results suggest that the failure of citalopram to reduce immobility time in DBA/2J and BALB/c mice is attributable to genotype-dependent impairment of 5-HT synthesis. Interstrain comparisons could probably be a useful strategy for understanding the mechanisms underlying the response to selective serotonin reuptake inhibitors.