Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice

Fletcher, Paul; Tampakeras, Maria; Sinyard, Judy; Slassi, Abdelmalik; Isaac, Methvin; Higgins, Guy A.

doi:10.1016/j.neuropharm.2009.05.011

Cited by 72 publications

(59 citation statements)

References 48 publications

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“…Also interesting regarding (2)-MBP's lack of effect on locomotion is that most 5-HT 2C receptor agonists decrease locomotion in rodents (Fletcher et al, 2009;Halberstadt et al, 2009;Canal et al, 2013). Several reports show that 5-HT 2C receptor-targeting compounds modulate the release of central dopamine, with agonists decreasing and antagonists or inverse agonists increasing dopamine release in an apparently neural system-dependent manner (Di Giovanni et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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Development of 5-HT 2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT 2C selective agonists also activate 5-HT 2A and/or 5-HT 2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT 2C receptor agonist, (2) 2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT 2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

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Section: Discussionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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“…The 5-HT2 knockout model has been suggested as an in vivo screening model for 5-HT2C receptor ligands [88].…”

Section: Brain 5-ht and Satietymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

266

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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“…CHL1-deficient mice showed reduced reactivity to novelty or external stimuli, but no anxiety-related behavior (Montag-Sallaz et al, 2002;Pratte et al, 2003;Morellini et al, 2007;Pratte and Jamon, 2009). Mice expressing only the non-edited or the fully-edited isoform of the 5-HT2c receptor display anxiety-or depression-like symptoms and 5-HT2c-receptor-deficient mice display reduced reactivity to a novel environment or external stimuli, as well as alterations in sleep, feeding and reward-associated behaviors (for review and references, see Heisler et al, 2007;Fletcher et al, 2009;Iwamoto et al, 2009;Mombereau et al, 2010;Pennanen et al, 2013). Alterations in sleep, feeding and reward-associated behaviors have so far not been reported for CHL1-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

“…The non-edited isoform and the partially edited isoforms exhibit pronounced or intermediate constitutive activity, whereas the fully edited isoform is not constitutively active and requires binding of serotonin for activation (Burns et al, 1997;Herrick-Davis et al, 1999;Niswender et al, 1999). Reduced reactivity to a novel environment and sensitivity to locomotor stimulants, as well as alterations in sleep, feeding and reward-associated behaviors are observed in 5-HT2c-receptor-deficient mice, whereas mice expressing the non-edited or fully-edited isoforms show anxiety and depression-like symptoms, respectively (for a review and references, see Heisler et al, 2007;Iwamoto et al, 2009;Fletcher et al, 2009;Mombereau et al, 2010;Pennanen et al, 2013). In humans, the 5-HT2c receptor has been associated with obesity as well as neurological and psychiatric disorders, such as schizophrenia, major depression, addiction, epilepsy, anxiety, sleep disorders, motor dysfunction and bipolar disorder (Berg et al, 2008;Lee et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice

Kleene

Chaudhary

Karl

et al. 2015

Journal of Cell Science

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The serotonergic system plays important roles in multiple functions of the nervous system and its malfunctioning leads to neurological and psychiatric disorders. Here, we show that the cell adhesion molecule close homolog of L1 (CHL1), which has been linked to mental disorders, binds to a peptide stretch in the third intracellular loop of the serotonin 2c (5-HT2c) receptor through its intracellular domain. Moreover, we provide evidence that CHL1 deficiency in mice leads to 5-HT2c-receptor-related reduction in locomotor activity and reactivity to novelty, and that CHL1 regulates signaling pathways triggered by constitutively active isoforms of the 5-HT2c receptor. Furthermore, we found that the 5-HT2c receptor and CHL1 colocalize in striatal and hippocampal GABAergic neurons, and that 5-HT2c receptor phosphorylation and its association with phosphatase and tensin homolog (PTEN) and β-arrestin 2 is regulated by CHL1. Our results demonstrate that CHL1 regulates signal transduction pathways through constitutively active 5-HT2c receptor isoforms, thereby altering 5-HT2c receptor functions and implicating CHL1 as a new modulator of the serotonergic system.

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Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice

Cited by 72 publications

References 48 publications

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Serotonin controlling feeding and satiety

Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice

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Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice

Cited by 72 publications

References 48 publications

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

Serotonin controlling feeding and satiety

Interaction between CHL1 and serotonin receptor 2c regulates signal transduction and behavior in mice

Contact Info

Product

Resources

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A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses