Abstract
Serotonin (5-hydroxytryptamine, 5-HT) dysfunction is associated with the pathophysiology of depression. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT biosynthesis, is believed to have essential role in many mental disorders, including depression. In the present study, we generated a rat model of depression by exposing the animals to stress, and the rats were then treated with paroxetine. The results indicated that the concentration of 5-HT in the brain and liver tissues were significantly lower in the rat model of depression than in healthy or treated rats. Immunohistochemical analyses of TPH1/2 showed less TPH1 and TPH2 expression, specifically TPH2, in the brain, liver and kidney of the depressive rats than in the healthy rats; In addition, the two TPH isoforms, TPH1 and TPH2, had different spatial distributions,the mRNAs of the TPH1/2 genes were significantly decreased and TPH1/2 were highly methylated in the depressive model rat, but treatment with paroxetine ameliorated the expression and methylation of TPH1/2. All together, stress was able to inhibit expression of TPH1/2 in brain tissue and decrease concentration of 5-HT, the mechanism maybe involve in increasing the methylation of TPH2 genes promoter; Paroxetine has a role in confronting the effect of stress in depressive rat model.
Highlights
Depression is a heritable neuropsychiatric syndrome with a high mortality
Stress was able to inhibit expression of TPH1/2 in brain tissue and decrease concentration of 5-HT, the mechanism maybe involve in increasing the methylation of TPH2 genes promoter; Paroxetine has a role in confronting the effect of stress in depressive rat model
Stress may inhibit production of 5-HT in the kidney of depressive model rats (Figure 1C). These results for the 5-HT level in our experiments were consistent with the neurotransmitter theory of depression, which proposes that 5-HT synthesis is decreased in the brains of patients with depression [23,24,25,26]
Summary
Depression is a heritable neuropsychiatric syndrome with a high mortality. It is a severe and recurrent psychiatric disorder that affects approximately 10% of people during their lifetime [1, 2], the aetiology of depression is still undefined. TPH acts as the rate-limiting enzyme in 5-HT synthesis [14,15,16, 18,19,20]. No substantial overlap has been reported between the expression of the TPH1 and TPH2 proteins in adults [20, 21], supporting the hypothesis that TPH1 primarily catalyzes the synthesis of peripheral 5-HT, whereas TPH2 functions primarily at central serotonergic neurons
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