Serotonin Activates the Hypothalamic-Pituitary-Adrenal Axis via Serotonin 2C Receptor Stimulation

Heisler, Lora K.; Pronchuk, Nina; Nonogaki, Katsunori; Zhou, Ligang; Raber, Jacob; Tung, L. Y. C.; Yeo, Giles S.H.; O’Rahilly, Stephen; Colmers, William F.; Elmquist, Joel K.; Tecott, Laurence H.

doi:10.1523/jneurosci.2584-06.2007

Cited by 248 publications

(187 citation statements)

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“…Gene knockout of 5-HT2C-R leads to a decrease in anxiety-like behavior on a variety of assays (Heisler et al, 2007a). These mice also exhibit significantly lesser DOI-or mCPP-induced activation of CRH-positive cells in the central nucleus of the amygdala and bed nucleus of the stria terminalis, and signs of CRH downregulation in the PVN of the hypothalamus (Heisler et al, 2007a(Heisler et al, , 2007b.…”

Section: -Ht2c Receptorsmentioning

confidence: 98%

“…Intra-amygdala (and in some cases systemic) administration of 5-HT1A-R agonists can attenuate both the behavioral and neuroendocrine responses to various stressors, including restraint, forced swim and conditioned fear stimuli (Krysiak et al, 2000;Li et al, 2006;Rittenhouse et al, 1992). Conversely, although mRNA for the receptor is not abundant in the paraventricular nucleus of the hypothalamus (Heisler et al, 2007b), 5-HT1A-R agonists such as 8-OH-DPAT injected directly into this structure stimulates the HPA-axis (Calogero et al, 1990(Calogero et al, , 1993Gilbert et al, 1988;Pan and Gilbert, 1992). A pro-HPA-axis action of 5-HT1A-Rs would be consistent with the observation that systemic administration of the 5-HT1A-R agonist flesinoxan increased cFos expression in corticotropin-releasing hormone (CRH)-labeled cells in the PVN of the hypothalamus (as well as the central nucleus of the amygdala) (Compaan et al, 1996(Compaan et al, , 1997.…”

Section: Role Of 5-ht1a Receptorsmentioning

confidence: 99%

“…Serotonin normally stimulates glucocorticoid release in part via an action on CRH neurons in the PVN (Calogero et al, 1990(Calogero et al, , 1993Fuller and Snoddy, 1980;Heisler et al, 2007b;Jorgensen et al, 1998Jorgensen et al, , 2002, but Heisler et al showed that this effect is lost in the 5-HT2C-R knockout mice and ablated in non-mutant mice systemically treated with the selective 5-HT2C-R antagonist RS 102221. Whether 5-HT2C-R inactivation would also inhibit stress-induced HPA-axis activation has not been reported; although one study showed a greater decrease in body weight in response to acute restraint stress in aged 5-HT2C-R knockout mice (ChouGreen et al, 2003).…”

Section: -Ht2c Receptorsmentioning

confidence: 99%

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

Holmes

2008

Neuroscience & Biobehavioral Reviews

239

165

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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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Section: -Ht2c Receptorsmentioning

confidence: 98%

Section: Role Of 5-ht1a Receptorsmentioning

confidence: 99%

Section: -Ht2c Receptorsmentioning

confidence: 99%

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

Holmes

2008

Neuroscience & Biobehavioral Reviews

239

165

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“…A possible mechanistic explanation for the connection between the CRH system and serotonin is supplied by a study which found that in rats, approximately half of the CRH-containing neurons in the paraventricular nucleus of the hypothalamus co-expressed 5-HT2C mRNA. Genetic inactivation of 5-HT2C downregulated CRH mRNA expression and blunted CRH and corticosterone release after 5-HT administration (Heisler et al, 2007).…”

Section: Introductionmentioning

confidence: 95%

Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus)

et al. 2015

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PostprintThis is the accepted version of a paper published in Aquatic Toxicology. This paper has been peerreviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the original published paper (version of record):Kellner, M., Porseryd, T., Porsch-Hallstrom, I., Hansen, S., Olsén, H. (2015) Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus).Aquatic Toxicology,[158][159][160][161][162][163][164][165][166][167][168][169][170] http://dx.doi.org/10.1016/j.aquatox. 2014.11.003 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. NOTICE: this is the author's version of a work that was accepted for publication in Aquatic Toxicology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Aquatic Toxicology, Vol. 158,[165][166][167][168][169][170] Abstract Selective Serotonin Re-uptake Inhibitors (SSRI) are mood-altering, psychotropic drugs commonly used in the treatment of depression and other psychological illnesses. Many of them are poorly degraded in sewage treatment plants and enter the environment unaltered. In laboratory studies, they have been demonstrated to affect a wide range of behaviours in aquatic organisms. In this study we investigated the effect of a three week exposure of 0.15 and 1.5 µg/l of the SSRI citalopram dissolved in the ambient water on the feeding behaviour in three-spine stickleback (Gasterosteus aculeatus). Feeding, measured as the number of attacks performed on a piece of frozen bloodworms during a 10 minute period, was reduced by 40-60% in fish exposed to both 0.15 and 1.5 µg/l citalopram. The effects of the environmentally relevant dose 0.15 µg/l on feeding, an important fitness characteristic, suggests that the ecological significance of environmental SSRI exposure may be pronounced.

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“…40,85,86,88 -90 Blockade of 5-HT 2C sites may, further, enhance sexual function and improve restorative slow wave sleep, 42,85,91 and antagonism of hypothalamic 5-HT 2C receptors facilitatory to the hypothalamo-pituitary-adrenocortical (HPA) axis abrogates its overstimulation by stress. 88 Underpinning interest in drugs that both block 5-HT 2C sites and suppress 5-HT reuptake is the fact that, in addition to mediating anxiogenic actions, 5-HT 2C receptors are the principal culprits transducing the disruption of sleep, sexual function, and appetite by SSRIs. 3,85,90 -93 Nefazodone has a 5-HT 2C antagonist/SRI profile but its blockade of H 1 receptors provokes sedation.…”

Section: Bimodal Antidepressants Acting As 5-ht 2c or 5-ht 2a Receptomentioning

confidence: 99%

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

Millan¹

2009

Neurotherapeutics

176

122

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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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Serotonin Activates the Hypothalamic-Pituitary-Adrenal Axis via Serotonin 2C Receptor Stimulation

Cited by 248 publications

References 61 publications

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

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

Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus)

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

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