Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice

Abstract

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.

Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression

“…In fact, several studies indicate an interaction of glucocorticoids and TPH2 or its functional genetic variants, respectively. 60,66,67 In healthy individuals without a history of depression, we were unable to detect an effect of TPH2 polymorphisms on the occurrence of MetS. This difference among patients and controls could be explained by the interaction of genetic polymorphisms in TPH2 and RUD aggravating the monoamine deficit, which leads to metabolic disorders.…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…Chronic infusions of the stress-and anxiety-related peptide CRF increased the ratio of Tph2 mRNA expression in the central core region of the dorsal part of the DR, which, among others, extends serotonergic terminals to both the central and basolateral amygdala as well as the medial PFC, whereas Sert mRNA expression was decreased in the midrostrocaudal part of the DR nucleus, which contains many amygdala-projecting neurons [145,153]. In a model of maladaptive stress responsivity, mice deficient in CRF receptor-2 failed to show robust stress-mediated adaptations, including elevations in Tph2 expression and increases in antiapoptotic factors [154].…”

A unifying framework for depression: Bridging the major biological and psychosocial theories through stress

“…Moreover, glucocorticoids also decrease the brain isoform of tryptophan hydroxylase (TPH 2) involved in the conversion of tryptophan to 5-OH-tryptophan; this also causes a reduction in serotonin. Furthermore, glucocorticoids augment the alternative pathway for tryptophan, catalyzed by indoleamine 2,3-dioxygenase (IDO), to produce excess quinolinic acid ( UIN), a neurotoxin [156,157], as reviewed by Herbert [35] and as discussed later in this paper. Glucocorticoids have also been implicated in various studies for downregulating and desensitizing serotonin receptors in the hippocampus, which, as already detailed, is a brain structure strongly implicated in depression (reviews by Joca and colleagues [84] and Flugge [158]).…”

“…Finally, via its effects on the serotonergic system, glucocorticoids cause a shi away from the serotonin-producing tryptophan pathway, to an alternate pathway for tryptophan, catalyzed by IDO, which produces excess UIN. Increased UIN production may cause excess stimulation of NMDA receptors, yielding neurotoxicity [156,157] (review by Herbert [35]). …”