Tissue specific regulation of rat tryptophan hydroxylase gene by stress: Role of the 5' untranslated region

We examined the effect of immobilization stress (IMO) on the gene expression of tryptophan hydroxylase (TPH), the rate limiting enzyme in serotonin biosynthesis. We quantified its mRNA levels in raphe nuclei and pineal gland of control and stressed rats by competitive RT-PCR. The effect of stress on TPH protein levels was determined using western blot analysis and immunocytochemistry. We observed a tissue specific induction in TPH mRNA and protein levels after stress administration. Repeated IMO (7x) triggered 10- or 6-fold increase in TPH mRNA in dorsal and median raphe nuclei (DRN and MRN respectively), but failed to elicit any induction in the pineal gland. TPH protein levels were also elevated by 5-fold in the brainstem raphe nuclei of rats exposed to 6x repeated IMO and were unaltered in the pineal gland. In addition, we determined that the observed TPH gene expression response to stress was impaired in rat model for depression, the Flinders Sensitive Line (FSL). Subsequent to their exposure to stress, FSL animals displayed no significant change in TPH mRNA levels in the brainstem. However, the basal levels of TPH mRNA in the brainstem of the FSL rats were high compared to normal rats and near those of stressed Sprague-Dawley rats used as controls.; This study elucidated that chronic stress exposure leads to elevated tryptophan hydroxylase gene expression in rat brainstem raphe nuclei as demonstrated by elevated TPH mRNA and protein levels. It also revealed the importance of the mRNA 5′ untranslated regions in regulating TPH gene expression. Furthermore, the elevated tryptophan hydroxylase gene expression in the animal models of depression may provide new insight to the molecular biology of depressive illness. (Abstract shortened by UMI.)...