Clinical Pharmacy & Pharmacology Research Institute, Second Xiangya Hospital, Central South University, Changsha, P.R. China.
Eur Rev Med Pharmacol Sci. 2013 Jan;17(1):41-8.
Venlafaxine is a new antidepressant that has a chemical structure and neuropharmacologic profile distinct from those of existing antidepressants. The studies about the mechanism of pharmacological action of venlafaxine mostly investigated the effects of venlafaxine on 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) levels, while only few studies examined the effects on the metabolites levels and ratio of these monoamines neurotransmitters.
To study the biochemical mechanism of venlafaxine through determining the metabolism of monoamine neurotransmitters in brain tissues of rat model of depression after administration of venlafaxine using metabonomic method.
The rat model of depression was established by using the methods of separation and chronic unpredictable stress. We have determined 5-HT, NE, DA and their metabolites, i.e., 5-hydroxyindole-3-acetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (MHPG) sulfate, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat brain tissues by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) following chronic administration of different venlafaxine doses (8, 16, 32 mg·kg-1) and saline solution for 14 days. Linear discriminant analysis (LDA) and principal components analysis (PCA) were used in data analysis of metabonomic.
Compared with saline, venlafaxine could significantly increase brain 5-HT and NE levels at middle dose (16 mg·kg-1) or high dose (32 mg·kg-1), especially at middle dose. These increases were greater than those seen with the comparable dose of selective serotonin reuptake inhibitor (SSRI), fluoxetine, under the same experimental conditions.
Venlafaxine lowers brain neurotransmitter metabolite levels by decreasing brain neurotransmitters turnover. Venlafaxine could correct the disorder of neurotransmitters' metabolism and coordinate the balance of 5-HT, NE and DA to reach the anti-depressed function.
文拉法辛是一种新型抗抑郁药，其化学结构和神经药理学特性与现有抗抑郁药不同。关于文拉法辛药理作用机制的研究大多集中在文拉法辛对 5-羟色胺（5-HT）、去甲肾上腺素（NE）和多巴胺（DA）水平的影响上，而只有少数研究考察了这些单胺神经递质代谢物水平和比率的影响。
通过代谢组学方法测定文拉法辛给药后抑郁大鼠模型脑组织中单胺神经递质的代谢，研究文拉法辛的生化机制。
采用分离和慢性不可预测应激的方法建立抑郁大鼠模型。我们已经通过液相色谱-电喷雾串联质谱法（LC-ESI-MS/MS）测定了大鼠脑组织中的 5-HT、NE、DA 及其代谢物，即 5-羟吲哚-3-乙酸（5-HIAA）、4-羟基-3-甲氧基苯乙二醇（MHPG）硫酸盐、3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA），在慢性给予不同剂量文拉法辛（8、16、32mg·kg-1）和生理盐水 14 天后。代谢组学数据采用线性判别分析（LDA）和主成分分析（PCA）进行分析。
与生理盐水相比，文拉法辛在中剂量（16mg·kg-1）或高剂量（32mg·kg-1）时能显著增加脑 5-HT 和 NE 水平，特别是在中剂量时。这些增加大于在相同实验条件下给予选择性 5-羟色胺再摄取抑制剂（SSRI）氟西汀相当剂量时的增加。
文拉法辛通过降低脑神经递质周转率降低脑神经递质代谢物水平。文拉法辛能纠正神经递质代谢紊乱，协调 5-HT、NE 和 DA 的平衡，达到抗抑郁作用。
