Ebselen has lithium‐like effects on central <scp>5‐HT<sub>2A</sub></scp> receptor function

Antoniadou, Ioanna; Kouskou, M; Arsiwala, Tasneem; Singh, Nisha; Vasudevan, Sridhar R.; Fowler, Thomas; Çadırcı, Elif; Churchill, Grant C.; Sharp, Trevor

doi:10.1111/bph.14179

Cited by 26 publications

(28 citation statements)

References 61 publications

(102 reference statements)

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“…Our previous studies (Singh et al, 2013; Antoniadou et al, 2018) identified that ebselen had various neuropharmacological actions similar to those reported for lithium in preclinical models, and the present study extends this to impulse control. Thus, in the 5-CSRTT, the inhibition of premature responding by ebselen was observed at more than one dose, and under conditions of elevated premature responding as induced by cocaine.…”

Section: Discussionsupporting

confidence: 85%

The putative lithium-mimetic ebselen reduces impulsivity in rodent models

et al. 2018

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Section: Discussionsupporting

confidence: 85%

The putative lithium-mimetic ebselen reduces impulsivity in rodent models

et al. 2018

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“…More recently, ebselen has been suggested as an antidepressant (Antoniadou et al 2018 ) and impulsivity lowering agent (Barkus et al 2018 ) based on its neuropharmacological lithium-like effects in different animal models of 5-HT2A function. Therefore, Fink and collaborators reported that elevated 5-HT2A receptor expression is associated with impulsive behavior in rodents (Fink et al 2015 ).…”

Section: Pharmacology Of Organoselenium Compoundsmentioning

confidence: 99%

Toxicology and pharmacology of synthetic organoselenium compounds: an update

2021

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Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.

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“…Nevertheless, it has been argued that the negative emotionality phenotype seen in 5-HTTKO mice is of neurodevelopmental origin rather than due to elevated 5-HT availability at the time of behavioral testing 30,31,46 . Citalopram causes a marked elevation of 5-HT availability, as shown by microdialysis 47 , and here we tested whether this elevation was sufficient to affect fear learning or memory. We did not use chronic SSRI administration because this can cause widespread changes to neuronal circuitry (e.g., increasing neurogenesis, altering the expression/function of other 5-HT receptors) 48,49 , and we wanted to test the effects of increasing 5-HT availability on fear learning/memory without these potential confounds.…”

Section: Discussionmentioning

confidence: 94%

Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice

et al. 2019

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Genetic variation in the human serotonin transporter (5-HTT) has been linked to altered fear learning but the data are inconsistent and the mechanism is unclear. The present study investigated conditioned aversive learning in 5-HTT knockout (KO) mice while simultaneously recording neural network activity (theta oscillations) and hemodynamic responses (tissue oxygen delivery) from the amygdala, a brain region necessary for forming fearful memories. Conditioned aversive learning was measured using a discrimination learning task in which one auditory cue was paired with foot-shock, whereas a second auditory cue was not. Compared with wild-type mice, 5-HTTKO mice exhibited faster discrimination learning. This effect was associated with stronger theta frequency oscillations and greater hemodynamic changes in the amygdala in response to both the emotionally relevant cues and the unconditioned foot-shock stimulus. Furthermore, hemodynamic responses to the unconditioned stimulus predicted behavioral discrimination performance the following day. Acute pharmacological 5-HTT blockade in wild-type mice produced a similar effect, to the extent that administration of citalopram during the fear conditioning sessions enhanced fear memory recall. Collectively, our data argue that loss of 5-HTT function enhances amygdala responsivity to aversive events and facilitates learning for emotionally relevant cues.

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Ebselen has lithium‐like effects on central 5‐HT_2A receptor function

Cited by 26 publications

References 61 publications

The putative lithium-mimetic ebselen reduces impulsivity in rodent models

The putative lithium-mimetic ebselen reduces impulsivity in rodent models

Toxicology and pharmacology of synthetic organoselenium compounds: an update

Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice

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Ebselen has lithium‐like effects on central 5‐HT2A receptor function

Cited by 26 publications

References 61 publications

The putative lithium-mimetic ebselen reduces impulsivity in rodent models

The putative lithium-mimetic ebselen reduces impulsivity in rodent models

Toxicology and pharmacology of synthetic organoselenium compounds: an update

Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice

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Ebselen has lithium‐like effects on central 5‐HT_2A receptor function