Biochemical mechanism studies of venlafaxine by metabonomic method in rat model of depression.

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.