Differential hormonal regulation of tryptophan hydroxylase-2 mRNA in the murine dorsal raphe nucleus

Clark, Janet A.; Pai, Lee-Yuh; Flick, Rosemarie B.; Rohrer, Susan P.

doi:10.1016/j.biopsych.2005.01.013

Cited by 53 publications

(40 citation statements)

References 19 publications

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“…It has been previously shown that glucocorticoids do not effect TPH1 mRNA expression in murine raphe nuclei 31 and so the glucocorticoid-mediated changes in serotonin biosynthesis observed here are most likely due to changes in expression levels of TPH2 protein, although a glucocorticoid effect on TPH1 protein turnover cannot be entirely ruled out. Steroid modulation of TPH2 protein is specific to the glucocorticoid receptor as co-administration of the glucocorticoid antagonist mifepristone blocked the effects of dexamethasone.…”

Section: Pitmentioning

confidence: 50%

“…31 We have now used TPH2-6361 to show glucocorticoid-specific regulation of TPH2 protein in murine raphe nuclei. These data represent the first to show isoform-specific glucocorticoid modulation of TPH protein in any species.…”

Section: Pitmentioning

confidence: 99%

“…31 We now describe the identification and characterization of TPH2-specific antiserum (TPH2-6361), which we have used to study TPH2 protein distribution in rodent and human brain. In addition, we used TPH2-6361 to show that glucocorticoid modulation of TPH2 mRNA is followed by changes in TPH2 protein expression in the murine raphe.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

Mol Psychiatry

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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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Section: Pitmentioning

confidence: 50%

Section: Pitmentioning

confidence: 99%

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

et al. 2007

Mol Psychiatry

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“…Further work will be needed to substantiate and extend this hypothesis. For example, because Tph2-mediated serotonin synthesis is known to be regulated by glucocorticoids in C57BL/6J (Clark et al, 2007;Clark et al, 2005) it would be of interest to examine whether this mechanism is impaired in strains with the low-expressing SNP such as DBA/2J and BALB/cJ (Table 1).…”

Section: Serotonin Synthesismentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

243

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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“…3,167,197,[202][203][204] The beneficial effects of GR antagonists and metyrapone involve a sustained induction of mineralocorticoid receptors, as well as serotonergic and dopaminergic mechanisms. 3,196,197,199,[205][206][207] Agents curtailing HPA overdrive may also abrogate deleterious somatic effects such as obesity, osteoporosis, and coronary artery disease. 3,196 Finally, GR antagonists hasten and augment the induction of 5-HT levels elicited by chronic fluoxetine, possibly by accelerating desensitization of 5-HT 1A autoreceptors.…”

Section: Innovative Neuroendocrine Mechanisms: Calming Hpa Axis Overdmentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

179

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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Differential hormonal regulation of tryptophan hydroxylase-2 mRNA in the murine dorsal raphe nucleus

Cited by 53 publications

References 19 publications

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

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

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

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