The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.
Considerable attention has focused on regulation of central tryptophan hydroxylase (TPH) activity and protein expression. At the time of these earlier studies, it was thought that there was a single central TPH isoform. However, with the recent identification of TPH2, it becomes important to distinguish between regulatory effects on the protein expression and activity of the two isoforms. We have generated a TPH2-specific polyclonal antiserum (TPH2-6361) to study regulation of TPH2 at the protein level and to examine the distribution of TPH2 expression in rodent and human brain. TPH2 immunoreactivity (IR) was detected throughout the raphe nuclei, in lateral hypothalamic nuclei and in the pineal body of rodent and human brain. In addition, a prominent TPH2-IR fiber network was found in the human median eminence. We recently reported that glucocorticoid treatment of C57/Bl6 mice for 4 days markedly decreased TPH2 messenger RNA levels in the raphe nuclei, whereas TPH1 mRNA was unaffected. The glucocorticoid-elicited inhibition of TPH2 gene expression was blocked by co-administration of the glucocorticoid receptor antagonist mifepristone (RU-486). Using TPH2-6361, we have extended these findings to show a dose-dependent decrease in raphe TPH2 protein levels in response to 4 days of treatment with dexamethasone; this effect was blocked by co-administration of mifepristone. Moreover, the glucocorticoid-elicited inhibition of TPH2 was functionally significant: serotonin synthesis was significantly reduced in the frontal cortex of glucocorticoid-treated mice, an effect that was blocked by mifepristone coadministration. This study provides further evidence for the glucocorticoid regulation of serotonin biosynthesis via inhibition of TPH2 expression, and suggest that elevated glucocorticoid levels may be relevant to the etiology of psychiatric diseases, such as depression, where hypothalamic-pituitary-adrenal axis dysregulation has been documented.
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