The putative lithium-mimetic ebselen reduces impulsivity in rodent models

Barkus, Christopher; Ferland, Jacqueline‐Marie N.; Adams, Wendy K.; Churchill, Grant C.; Cowen, Philip J.; Bannerman, David M.; Rogers, Robert D.; Winstanley, Catharine A.; Sharp, Trevor

doi:10.1177/0269881118784876

Cited by 23 publications

(12 citation statements)

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“…While the serotonin system is notoriously complex, comprising over 14 receptor subtypes (Barnes and Sharp, 1999), the 5-HT 2A and 5-HT 2c receptors play a prominent role in regulating impulsivity where they appear to play opposing roles. Antagonism of the 5-HT 2A receptor with M100 907 (Barkus et al, 2018; Fletcher et al, 2007, 2011; Nikiforuk et al, 2015; Winstanley et al, 2003, 2004b) or ketanserin (Fletcher et al, 2007; Passetti et al, 2003) or reducing 5-HT 2A function via ebselen (Barkus et al, 2018) reliably decreases premature responding on the 5-CSRTT. Similar reductions in impulsive action are observed following M100907 on the rodent gambling task (rGT): a decision-making task whose design is loosely based on the 5-CSRTT (Adams et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats

et al. 2020

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Background: Individuals must frequently evaluate whether it is worth allocating cognitive effort for desired outcomes. Motivational deficits are a common feature of psychiatric illness such as major depression. Selective serotonin reuptake inhibitors are commonly used to treat this disorder, yet some data suggest these compounds are ineffective at treating amotivation, and may even exacerbate it. Aims: Here we used the rodent Cognitive Effort Task (rCET) to assess serotonergic (5-hydroxytryptamine, 5-HT) contributions to decision-making with cognitive effort costs. Methods: The rCET is a modified version of the 5-choice serial reaction time task, a well-validated test of visuospatial attention and impulse control. At the start of each rCET trial, rats chose one of two levers, which set the difficulty of an attentional challenge, namely the localization of a visual stimulus illuminated for 0.2 or 1 s on hard versus easy trials. Successful completion of hard trials was rewarded with double the sugar pellets. Twenty-four female Long–Evans rats were trained on the rCET and systemically administered the 5-HT1A agonist 8-OH-DPAT, the 5-HT2A antagonist M100907, the 5-HT2C agonist Ro-60-0175, as well as the 5-HT2C antagonist SB 242, 084. Results: 5-HT2A antagonism dose-dependently reduced premature responding, while 5-HT2C antagonism had the opposite effect. 8-OH-DPAT impaired accuracy of target detection at higher doses, while Ro-60-0175 dose-dependently improved accuracy on difficult trials. However, none of the drugs affected the rats’ choice of the harder option. Conclusion: When considered with existing work evaluating decision-making with physical effort costs, it appears that serotonergic signalling plays a minor role in guiding effort allocation.

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Section: Discussionmentioning

confidence: 99%

Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats

et al. 2020

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“…Although the mechanism behind this effect of 5-HT 2A receptor blockade is not certain, it may link to evidence of an inhibitory 5-HT 2A receptor-mediated feedback on 5-HT neurons (Sharp et al, 2007). Interestingly, the 5-HT 2A receptor has also been associated with impulse control; thus, selective 5-HT 2A receptor antagonists consistently decrease impulsivity in animal models (Winstanley et al, 2004;Winstanley, 2011;Barkus et al, 2018) and this is supported by psychopharmacological studies in humans using the non-selective 5-HT 2A receptor antagonist quetiapine (Rock et al, 2013). In this regard it is noteworthy that lithium and the repurposed lithium-mimetic ebselen are both reported to attenuate 5-HT 2A receptor function, likely via inhibition of the phosphoinositide pathway (Singh et al, 2013;Antoniadou et al, 2018).…”

Section: -Ht 2a Receptorsmentioning

confidence: 99%

Central 5-HT receptors and their function; present and future

2020

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“…Nevertheless, previous studies that investigated drugs that affect 5-HT 2A receptors have shown similar results to ours. Both M100907, a 5-HT 2A receptor specific antagonist, and the lithium-mimetic ebselen, known to dampen 5-HT 2A -related intracellular signaling, failed to show any effects on the rodent gambling task in rats (Adams et al, 2017;Barkus et al, 2018). Similar results on decision making behaviors together with psychedelic drugs have also been observed in humans.…”

Section: Discussionmentioning

confidence: 60%

Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task

et al. 2020

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While interest in psychedelic drugs in the fields of psychiatry and neuroscience has re-emerged in recent last decades, the general understanding of the effects of these drugs remains deficient. In particular, there are gaps in knowledge on executive functions and goal-directed behaviors both in humans and in commonly used animal models. The effects of acute doses of psychedelic lysergic acid diethylamide (LSD) on reward-driven decision making were explored using the mouse version of the Iowa Gambling Task. A total of 15 mice were trained to perform in a touch-screen adaptation of the rodent version of the Iowa Gambling Task, after which single acute doses of LSD (0.025, 0.1, 0.2, 0.4 mg/kg), serotonin 2A receptor-selective agonist 25CN-NBOH (1.5 mg/kg), d-amphetamine (2.0 mg/kg), and saline were administered before the trial. 25CN-NBOH and the three lowest doses of LSD showed no statistically significant changes in option selection or in general functioning during the gambling task trials. The highest dose of LSD (0.4 mg/kg) significantly decreased premature responding and increased the omission rate, but had no effect on option selection in comparison with the saline control. Amphetamine significantly decreased the correct responses and premature responding while increasing the omission rate. In conclusion, mice can perform previously learned, reward-driven decision-making tasks while under the acute influence of LSD at a commonly used dose range.

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The putative lithium-mimetic ebselen reduces impulsivity in rodent models

Cited by 23 publications

References 50 publications

Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats

Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats

Central 5-HT receptors and their function; present and future

Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task

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