Inactivation of 5-HT2C Receptors Potentiates Consequences of Serotonin Reuptake Blockade

Cremers, Thomas; Giorgetti, Marco; Bosker, Fokko J.; Hogg, Sandy; Arnt, Jørn; Mørk, Arne; Honig, Gerard; Bøgesø, Klaus-Peter; Westerink, Ben H.C.; Boer, H.; Wikström, Håkan; Tecott, Laurence H.

doi:10.1038/sj.npp.1300474

Cited by 147 publications

(96 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although 5-HT 2C receptor antagonists potentiated the actions of SSRIs, they had no effect on extracellular 5-HT levels or tail suspension responses when administered alone. These results corresponded well with independent findings using a line of 5-HT 2C receptor null mutant mice [165]. Although this mutation did not affect baseline extracellular 5-HT levels or tail suspension test (TST) behaviour, it enhanced fluoxetineinduced effects on 5-HT levels and immobility in the TST.…”

Section: -Ht 2c Recptors and Depressionsupporting

confidence: 78%

“…[165,166]. Thus, agomelatine, the first melatonergic antidepressant with 5-HT 2C antagonist properties, was observed to produce a robust augmentation of citalopram-, fluoxetine-, and sertraline-induced elevations of hippocampal extracellular 5-HT levels [165,166]. The potentiation of SSRI-induced increases in hippocampal 5-HT levels was reproduced by the 5-HT 2C receptor-selective antagonists SB 242084 and RS 102221, but not by the 5-HT 2A receptor-selective antagonist MDL 100,907.…”

Section: -Ht 2c Recptors and Depressionmentioning

confidence: 99%

See 1 more Smart Citation

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

View full text Add to dashboard Cite

Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action is underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified. This review was undertaken to summarize the work that has explored the pathophysiological role of one of these receptors, the 5-HT 2C receptor, that has been emerged as a prominent central serotonin receptor subtype. The physiology, pharmacology and anatomical distribution of the 5-HT 2C receptors in the CNS will be firstly reviewed. Finally, their potential involvement in the pathophysiology of depression, schizophrenia, Parkinson's disease and drug abuse will be also discussed.Keywords: Serotonergic receptors, Depression, Schizophrenia, Drug of abuse, selective 5-HT 2C drugs. BASIC ANATOMY OF 5-HT SYSTEMMore than fifty years have passed since Twarog and Page [1] isolated an indole, identified as serotonin (5-HT), in the mammalian brain. Subsequently, Brodie and colleagues [2] suggested that 5-HT might serve as a neurotransmitter in the central nervous system (CNS). The result was one of the most important discoveries in science, giving birth to a new branch of neuroscience [3]. Serotonin is one of the oldest biologically active compound on earth, found in a variety of plants and animals. In vertebrates, the majority of the neurons containing 5-HT are grouped in 9 nuclei named B1 to B9, located in the medial part of the brainstem, generically called the raphe nuclei [4] (Fig. 1). These midline clusters can be divided into two major groups. The caudal or inferior group, localized in the medulla, contains the three nuclei projecting essentially to the grey matter of the spinal cord: the nucleus raphe magnus (NRM, cell group B5), nucleus raphe obscurus (NRO, cell groups B1-B2-B3), and nucleus raphe pallidus (NRP, cell group B4). The rostral or superior group, situated in the pons/mesenchephalon, contains the dorsal raphe nucleus (DRN, cell groups B6 and B7) and the median raphe nucleus (MRN, cell group B8). These nuclei supply about 80% of the serotonergic innervation of the forebrain. Even if in many brain areas, the innervation coming from the two nuclei overlaps, in certain regions the innervation comes exclusively or prevalently from one nucleus only. For example, the dorsal hippocampus receives a serotonergic innervation only from MRN, other areas innervated preferentially from this nucleus are: the medial preoptic area, the suprachiasmatic nucleus, the olfactory bulb *Address correspondence to this author at the Istituto di Ricerche Farmacologiche "Mario Negri", Consor...

show abstract

Section: -Ht 2c Recptors and Depressionsupporting

confidence: 78%

Section: -Ht 2c Recptors and Depressionmentioning

confidence: 99%

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

View full text Add to dashboard Cite

show abstract

“…Interestingly, the augmentation of 5-HT with the combination of citalopram and 5-HT 2C receptor antagonists was of similar magnitude as previously reported for compounds that block 5-HT 1A and 5-HT 1B autoreceptors (Cremers et al, 2000a(Cremers et al, , b, 2001(Cremers et al, , 2004. However, the current mechanism of augmentation is more complex, as 5-HT 2C receptors are not located on serotonergic neurons (see below).…”

Section: Discussionsupporting

confidence: 79%

“…Our group recently reported on the acute augmentation of 5-HT levels by combining SSRIs with 5-HT 2C antagonists (Cremers et al, 2004). The 5-HT 2C receptor antagonist SB242084 was chosen as it has a 100-fold affinity over other 5-HT receptors (Kennett et al, 1997;Bromidge et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

Cremers

Rea

Bosker

et al. 2007

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

The treatment of depression may be improved by using an augmentation approach involving selective serotonin reuptake inhibitors (SSRIs) in combination with compounds that focus on antagonism of inhibitory serotonin receptors. Using microdialysis coupled to HPLC, it has recently been shown that the systemic co-administration of 5-HT 2C antagonists with SSRIs augmented the acute effect of SSRIs on extracellular 5-HT. In this paper, we have investigated the mechanism through which this augmentation occurs. The increase in extracellular 5-HT was not observed when both compounds were locally infused. However, varying the route of administration for both compounds differentially revealed that an augmentation took place when the 5-HT 2C antagonist was locally infused into ventral hippocampus and the SSRI given systemically, but not when systemic 5-HT 2C antagonist was co-administered with the local infusion of citalopram. This suggests that the release of extracellular serotonin in ventral hippocampus may be controlled by (an)other brain area(s). As 5-HT 2C receptors are not considered to be autoreceptors, this would implicate that other neurotransmitter systems are involved in this process. To investigate which neurotransmitter systems were involved in the interaction, systemic citalopram was challenged with several glutamatergic, GABA-ergic, noradrenergic, and dopaminergic compounds to determine their effects on serotonin release in ventral hippocampus. It was determined that the involvement of glutamate, norepinephrine, and dopamine in the augmentation did not seem likely, whereas evidence implicated a role for the GABA-ergic system in the augmentation.

show abstract

“…However, either 5-HT2C-R gene knockout or systemic treatment with the selective 5-HT2C-R antagonists SB 242084 or RS 102221 has been shown to both potentiate the antidepressant-related effects of SRIs in the tail suspension test and augment the increases in cortical and hippocampal ECF serotonin levels produced by SRI treatment (Cremers et al, 2004(Cremers et al, , 2007. On the other hand, systemic treatment with the novel 5-HT2C-R agonists WAY 163909, RO 600175 also exert antidepressant-like effects in a range of rodent assays (Cryan and Lucki, 2000;Martin et al, 1998;Rosenzweig-Lipson et al, 2007).…”

Section: -Ht2c Receptorsmentioning

confidence: 99%

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

Holmes

2008

Neuroscience & Biobehavioral Reviews

239

166

View full text Add to dashboard Cite

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.

show abstract

Inactivation of 5-HT2C Receptors Potentiates Consequences of Serotonin Reuptake Blockade

Cited by 147 publications

References 34 publications

Central Serotonin2C Receptor: From Physiology to Pathology

Central Serotonin2C Receptor: From Physiology to Pathology

Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

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

Contact Info

Product

Resources

About