Effect of the 5-HT2C Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study

Whitestone, Sara; Deurwaerdère, Philippe De; Baassiri, Lynn; Manem, Julien; Anouar, Youssef; Giovanni, Giuseppe Di; Bharatiya, Rahul; Chagraoui, Abdeslam

doi:10.3390/ijms20122925

Cited by 12 publications

(14 citation statements)

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“…The study revealed the highest effects in the amygdala, hypothalamus, and the relationships between cortical areas and subcortical regions. Thus, these results further confirm that 5-HT 2C R activation exerts widespread effects in the brain ( Chagraoui et al, 2019 ; Whitestone et al, 2019 ; De Deurwaerdere et al, 2020a ) and suggests that the effects on NA and 5-HT systems play a role in lorcaserin effects.…”

Section: Discussionsupporting

confidence: 75%

“…The effects are more tangible with lorcaserin especially for NA for which WAY-163909 did not modify the tissue content in all these brain regions ( Chagraoui et al, 2019 ). Irrespective of the monoamine involved, the CE is the only brain region where neurochemical changes of monoamines have been found with the two agonists, and already at the lowest dose ( Chagraoui et al, 2019 ; Whitestone et al, 2019 ). This points out that one of the most critical 5-HT 2C R roles is modulating the amygdala activity ( Hackler et al, 2006 ; Moya et al, 2011 ; Regue et al, 2019 ; van de Wouw et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Using postmortem analysis of monoamine tissue contents in a broad number of brain areas, it was found that the preferential 5-HT 2C R agonist WAY-163909 poorly altered monoamines content quantitatively, but induced changes in the pattern of correlations between pairs of brain regions for monoamines, monoamine metabolism, between monoamines, and between their metabolism ( Chagraoui et al, 2019 ; Whitestone et al, 2019 ). A similar neurochemical pattern with lorcaserin has been produced recently to determine its action on DA post-mortem index across the brain ( De Deurwaerdere et al, 2020a ), allowing us to determine whether it alters NA and 5-HT systems alone or in interaction with the DA systems.…”

Section: Introductionmentioning

confidence: 99%

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Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain

et al. 2020

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Lorcaserin is a preferential serotonin2C receptor (5-HT 2C R) agonist effective to treat obesity that has also recently been proposed to treat addiction and epilepsy. Central dopamine (DA) mechanisms are likely involved in the lorcaserin mechanism of action, but other monoamines 5-HT and noradrenaline (NA) contents or their interaction with DA might account for its effects. Here we showed that lorcaserin at 3, but not 0.3 mg/kg enhanced 5-HT content in the insular cortex, the core of the nucleus accumbens, and ventral hypothalamus. Without affecting the metabolite 5-hydroxy indole acetic acid, lorcaserin reduced the indirect index of 5-HT turnover in the hippocampus, substantia nigra, and habenula. Lorcaserin at 3 mg/kg increased NA content in the orbitofrontal cortex, the central amygdala (also at 0.3 mg/kg), the ventral hypothalamus, and the shell of the nucleus accumbens. A correlative analysis of the tissue contents between pairs of brain regions revealed that 0.3 mg/kg lorcaserin enhanced the number of correlations for 5-HT, its metabolism, and NA to a lower extent. The correlation profiles were very different between saline, 0.3 and 3 mg/kg lorcaserin. Lorcaserin enhanced the correlations established between NA or 5-HT at 0.3 and 3 mg/kg and reduced the number of correlations established between the index of the turnover for DA and 5-HT. These results show that lorcaserin modulates the biochemistry of NA and 5-HT systems in a subset of brain regions. Qualitatively, they reveal, oppositely to the DA changes, that lorcaserin at 0.3, but not 3 mg/kg, enhanced the number of correlations of 5-HT content between brain regions.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain

et al. 2020

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“…Indeed, we found reduced levels of a serotonin metabolite 5-HIAA and the 5-HIAA/serotonin ratios, as well as their increase at week 2 of stress. The 5-HIAA/serotonin ratio is common biomarker of CNS serotonergic activity, reflecting the activation of serotonergic neurons and their serotonin release, followed by its metabolization 65,66 . Interestingly, our findings also parallel reduced 5-HIAA in 15-day zebrafish CUS reported in a different study earlier 67 .…”

Section: Discussionmentioning

confidence: 99%

Understanding complex dynamics of behavioral, neurochemical and transcriptomic changes induced by prolonged chronic unpredictable stress in zebrafish

Demin

Lakstygal

Krotova

et al. 2020

Sci Rep

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Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy.

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“…45 More contemporary preclinical studies, using tissue sampling method, described increased 5-HT concentration in the orbitofrontal cortex, motor cortex-2, as well as increased DA turnover in the medial orbitofrontal cortex, in direct response to administration of 5-HT 2C selective agonist. 47,48 In aggregate, literature instantiates a plausible explanation for impact of 5-HT 2C agonism on change in 5-HT and DA transmission (as well as their relative balance) in brain pathways and regions relevant for impulse control, Figure 5 Complex regulation of 5-HT projections to prefrontal cortex. 1.…”

Section: Mechanism Of Action Of Viloxazinementioning

confidence: 99%

<p>New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties</p>

Yu¹,

Garcia‐Olivares²,

Candler³

et al. 2020

JEP

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Background: Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy. Methods: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats. Results: We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT 2B and agonistic activity at 5-HT 2C receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems. Conclusion: Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).

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Effect of the 5-HT2C Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study

Cited by 12 publications

References 72 publications

Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain

Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain

Understanding complex dynamics of behavioral, neurochemical and transcriptomic changes induced by prolonged chronic unpredictable stress in zebrafish

<p>New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties</p>

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