New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders

Giovanni, Giuseppe Di; Deurwaerdère, Philippe De

doi:10.1016/j.pharmthera.2015.11.009

Cited by 102 publications

(99 citation statements)

References 580 publications

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“…Activation of the 5-HT 2C Rs do not appear to play a pivotal role in focal epilepsy or on the contrary is proepileptic (Di Giovanni and De Deurwaerdere, 2016). Indeed, 5-HT 2C R agonists with different pharmacological profiles such as meta-chlorophenylpiperazine (mCPP) and lorcaserin, but not RO60-0175, were able to stop the elongation of the electrically triggered hippocampal maximal dentate gyrus activation in a limbic seizure model in anesthetized rats, an effect that was not blocked but rather potentiated by pre-treatment of SB 242084 (Orban et al, 2014), a selective 5-HT 2C R antagonist.…”

Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencementioning

confidence: 99%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

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A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

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Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencementioning

confidence: 99%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

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“…Furthermore, a growing body of human studies suggests that serotonergic neurons appreciably contribute to the development of psychiatric side effects induced by CB 1 receptor antagonists [3]. At the same time, the key role of different 5-HT 2 receptor subtypes has been demonstrated in the regulation of neuronal excitability, sleepwake cycle, and also in the control of anxiety and locomotor activity [4,5]. The link between eCB system and locomotor regulation is shown by the fact that psychomotor performance of chronic cannabis smokers during abstinence is decreased [6], presumably as a result of the downregulation of CB 1 receptors and eCB dysfunction in cortical areas and in basal ganglia [7,8].…”

Section: Introductionmentioning

confidence: 99%

Blockade of Serotonin 2C Receptors with SB-242084 Moderates Reduced Locomotor Activity and Rearing by Cannabinoid 1 Receptor Antagonist AM-251

et al. 2019

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The endocannabinoid and serotonin (5-HT) systems have key roles in the regulation of several physiological functions such as motor activity and food intake but also in the development of psychiatric disorders. Here we tested the hypothesis, whether blockade of serotonin 2C (5-HT_2C) receptors prevents the reduced locomotor activity and other behavioral effects caused by a cannabinoid 1 (CB₁) receptor antagonist. As a pretreatment, we administered SB-242084 (1 mg/kg, ip.), a 5-HT_2C receptor antagonist or vehicle (VEH) followed by the treatment with AM-251 (5 or 10 mg/kg, ip.), a CB₁ receptor antagonist or VEH. The effects of the two drugs alone or in co-administration were investigated in social interaction (SI) and elevated plus maze (EPM) tests in male Wistar rats. Our results show that AM-251 decreased the time spent with rearing in the SI test and decreased locomotor activity in EPM test. In contrast, SB-242084 produced increased locomotor activity in SI test and evoked anxiolytic-like effect in both SI and EPM tests. When applied the drugs in combination, these behavioral effects of AM-251 were moderated by SB-242084. Based on these findings, we conclude that certain unwanted behavioral effects of CB₁ receptor antagonists could be prevented by pretreatment with 5-HT_2C receptor antagonists.

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“…5-HT2CRs, via GABAergic feedback mechanisms, are also implicated in anxiety-like behaviours (Spoida et al 2014). As altered 5-HT2C-activity may be involved in abnormal feedback reactivity and associated symptoms, drugs with affinity for 5-HT2CRs represent therapeutic candidates for treating symptoms associated with MDD (Opal et al 2014; Di Giovanni and De Deurwaerdère 2016). …”

Section: Introductionmentioning

confidence: 99%

Selective effects of 5-HT2C receptor modulation on performance of a novel valence-probe visual discrimination task and probabilistic reversal learning in mice

et al. 2018

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RationaleDysregulation of the serotonin (5-HT) system is a pathophysiological component in major depressive disorder (MDD), a condition closely associated with abnormal emotional responsivity to positive and negative feedback. However, the precise mechanism through which 5-HT tone biases feedback responsivity remains unclear. 5-HT2C receptors (5-HT2CRs) are closely linked with aspects of depressive symptomatology, including abnormalities in reinforcement processes and response to stress. Thus, we aimed to determine the impact of 5-HT2CR function on response to feedback in biased reinforcement learning.MethodsWe used two touchscreen assays designed to assess the impact of positive and negative feedback on probabilistic reinforcement in mice, including a novel valence-probe visual discrimination (VPVD) and a probabilistic reversal learning procedure (PRL). Systemic administration of a 5-HT2CR agonist and antagonist resulted in selective changes in the balance of feedback sensitivity bias on these tasks.ResultsSpecifically, on VPVD, SB 242084, the 5-HT2CR antagonist, impaired acquisition of a discrimination dependent on appropriate integration of positive and negative feedback. On PRL, SB 242084 at 1 mg/kg resulted in changes in behaviour consistent with reduced sensitivity to positive feedback. In contrast, WAY 163909, the 5-HT2CR agonist, resulted in changes associated with increased sensitivity to positive feedback and decreased sensitivity to negative feedback.ConclusionsThese results suggest that 5-HT2CRs tightly regulate feedback sensitivity bias in mice with consequent effects on learning and cognitive flexibility and specify a framework for the influence of 5-HT2CRs on sensitivity to reinforcement.Electronic supplementary materialThe online version of this article (10.1007/s00213-018-4907-7) contains supplementary material, which is available to authorized users.

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New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders

Cited by 102 publications

References 580 publications

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Blockade of Serotonin 2C Receptors with SB-242084 Moderates Reduced Locomotor Activity and Rearing by Cannabinoid 1 Receptor Antagonist AM-251

Selective effects of 5-HT2C receptor modulation on performance of a novel valence-probe visual discrimination task and probabilistic reversal learning in mice

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