Neurochemical impact of the 5-HT2C receptor agonist WAY-163909 on monoamine tissue content in the rat brain

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

doi:10.1016/j.neuint.2019.01.019

Cited by 20 publications

(38 citation statements)

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“…Finally, even the same receptor subtype can trigger distinct responses on anxious states. 5-HT 2C R agonists, which act on monoaminergic transmission in various brain regions [33,131], can display no effect or trigger anxiogenic or panicolytic profiles depending on the laboratory tests used and the brain location of action [173]. Conversely, 5-HT 2C R antagonists exhibit an anxiolytic profile in several but not all behavioral paradigms [173,174].…”

Section: Anxietymentioning

confidence: 99%

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Serotonin in Animal Cognition and Behavior

Bacqué-Cazenave

Bharatiya

Barrière

et al. 2020

IJMS

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177

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Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator of nervous systems in both invertebrates and vertebrates. It has been proposed for several decades that it impacts animal cognition and behavior. In spite of a completely distinct organization of the 5-HT systems across the animal kingdom, several lines of evidence suggest that the influences of 5-HT on behavior and cognition are evolutionary conserved. In this review, we have selected some behaviors classically evoked when addressing the roles of 5-HT on nervous system functions.In particular, we focus on the motor activity, arousal, sleep and circadian rhythm, feeding, social interactions and aggressiveness, anxiety, mood, learning and memory, or impulsive/compulsive dimension and behavioral flexibility. The roles of 5-HT, illustrated in both invertebrates and vertebrates, show that it is more able to potentiate or mitigate the neuronal responses necessary for the fine-tuning of most behaviors, rather than to trigger or halt a specific behavior. 5-HT is, therefore, the prototypical neuromodulator fundamentally involved in the adaptation of all organisms across the animal kingdom.The organization of the 5-HT systems is completely different between species ranging from a limited number of cells in Aplysia or Drosophila (100 5-HT immunoreactive cells) to several thousand neurons in vertebrates. The variety and the heterogeneity of 5-HT neurons have been highlighted in vertebrates [7] as well as in invertebrates [8]. In general, the 5-HT systems in animals comprise 5-HT neurons, which share a particular shape made of thousands of varicosities, leading to the concept of volume transmission [9], and several 5-HT receptors (5-HTRs). In vertebrates, 5-HT neurons are localized in the midbrain raphe nuclei described as the B1-B9 cell groups [1,10]. The raphe pallidus, obscurus, and pontis form a caudal cluster (B1-B5), whereas the dorsal raphe and median raphe form a rostral cluster in the pons (B6-B9) [11]. The caudal raphe group projects to the spinal cord and the rostral group to the forebrain via an extensive and diffuse innervation. The dorsal raphe nucleus contains the highest number of 5-HT neurons and its anatomical sub-regions display some degrees of specific innervation of the forebrain [12][13][14]. The median and dorsal raphe nuclei receive excitatory and inhibitory inputs from most brain areas [15]. In crustaceans or insects, 5-HT neurons are widely present in each of the ventral cord ganglia, display large local ramifications that act in multiple neuropil areas, and some axonal branches form three pairs of rostrocaudal fibers [16][17][18][19]. Presumably, two of those fibers would project anteriorly and one posteriorly to the entire nervous system [20]. 5-HT neurons are often localized close to sensory integration input area in the brain of arthropods and some 5-HT cells in the abdominal ganglia of crayfish nerve cord are sensitive to the mechanical stimulation of abdominal segmental fringe hairs [21]. In cnidarians, 5-HT cells ...

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Section: Anxietymentioning

confidence: 99%

“…In mammals, the highest quantities of 5-HT are found in the substantia nigra (500-1000 pg/mg), followed by ventral tegmental area and raphe nuclei. Moderate to high quantities are found in other brain regions and spinal cord [33][34][35][36][37]. In chicken, the 5-HT content is higher in the amygdala compared to the thalamus or the striatum [38].…”

mentioning

confidence: 99%

Serotonin in Animal Cognition and Behavior

Bacqué-Cazenave

Bharatiya

Barrière

et al. 2020

IJMS

Self Cite

177

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“…44,45 Hence, the final outcome of 5-HT 2C stimulation will be influenced by local biochemical environment and relative density and activation of opposing sub-populations of 5-HT 2C receptors. 46,47 Subcortical 5-HT 2C receptors may have a pivotal role in modulating ascending nigrostriatal and mesocorticolimbic dopamine projections. Here are a few notable findings: stimulation of 5-HT 2C receptors facilitates DA release in the striatum, while intra-PFC administration of 5HT 2C agonists enhances dopaminergic transmission in Acb, induced by cocaine.…”

Section: Mechanism Of Action Of Viloxazinementioning

confidence: 99%

“…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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“…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%

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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Neurochemical impact of the 5-HT2C receptor agonist WAY-163909 on monoamine tissue content in the rat brain

Cited by 20 publications

References 70 publications

Serotonin in Animal Cognition and Behavior

Serotonin in Animal Cognition and Behavior

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

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

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