P.2.d.003 The novel multimodal antidepressant Lu AA21004 improves memory performance in 5-HT depleted rats via 5-HT3 and 5-HT1A receptor mechanisms

Pehrson, Alan L.; Nielsen, K.; Jensen, Jesper Bornø; Sánchez, Cristina

doi:10.1016/s0924-977x(12)70405-4

Cited by 6 publications

(8 citation statements)

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“…Additionally, 5-HT depletion-induced memory deficits were dose-dependently reversed by vortioxetine treatment, 106 while escitalopram and duloxetine were inactive. These data strongly suggest that the receptor activities of vortioxetine contribute to its cognition-improving properties in rats 106 . In further support of the relevance of the receptor mechanism, this study reported improved memory performance in rats by a selective 5-HT 1A receptor agonist and a 5-HT 3 receptor antagonist 106 .…”

Section: Multimodal Antidepressantsmentioning

confidence: 94%

“…This mechanism may explain previous reports that 5-HT 3 receptor antagonism by ondansetron enhances long-term potentiation (LTP) and hippocampal and cortical theta rhythms. 102,103 Likewise, 5-HT 3 receptor antagonists also improve memory 102,[104][105][106][107] in preclinical studies. For example, the 5-HT 3 receptor antagonist itasetron showed memory-enhancing effects in a multiple-choice avoidance behavioral task, 104 and ondansetron blocks scopolamine-induced deficits in learning.…”

Section: -Ht 3 Receptorsmentioning

confidence: 99%

“…146,147 Recently, it was reported that vortioxetine enhanced time-dependent contextual fear memory and object recognition memory in rats. 148 Additionally, 5-HT depletion-induced memory deficits were dosedependently reversed by vortioxetine treatment, 106 while escitalopram and duloxetine were inactive.…”

Section: Multimodal Antidepressantsmentioning

confidence: 99%

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Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

2013

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Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction.

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Section: Multimodal Antidepressantsmentioning

confidence: 94%

Section: -Ht 3 Receptorsmentioning

confidence: 99%

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Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

2013

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“…The 5-HTR 3 antagonists, such as ondansetron, are mainly used for the treatment of chemotherapy-induced emesis [ 101 ]. However, they have been also shown to improve cognition in different models of memory impairment [ 102 ]. Boast et al .…”

Section: Serotonin Receptors (5-htr)mentioning

confidence: 99%

The serotonergic system and cognitive function

Štrac

Pivac

Mück‐Šeler

2016

Translational Neuroscience

210

108

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Symptoms of cognitive dysfunction like memory loss, poor concentration, impaired learning and executive functions are characteristic features of both schizophrenia and Alzheimer’s disease (AD). The neurobiological mechanisms underlying cognition in healthy subjects and neuropsychiatric patients are not completely understood. Studies have focused on serotonin (5-hydroxytryptamine, 5-HT) as one of the possible cognitionrelated biomarkers. The aim of this review is to provide a summary of the current literature on the role of the serotonergic (5-HTergic) system in cognitive function, particularly in AD and schizophrenia.The role of the 5-HTergic system in cognition is modulated by the activity and function of 5-HT receptors (5-HTR) classified into seven groups, which differ in structure, action, and localization. Many 5-HTR are located in the regions linked to various cognitive processes. Preclinical studies using animal models of learning and memory, as well as clinical in vivo (neuroimaging) and in vitro (post-mortem) studies in humans have shown that alterations in 5-HTR activity influence cognitive performance.The current evidence implies that reduced 5-HT neurotransmission negatively influences cognitive functions and that normalization of 5-HT activity may have beneficial effects, suggesting that 5-HT and 5-HTR represent important pharmacological targets for cognition enhancement and restoration of impaired cognitive performance in neuropsychiatric disorders.

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“…The implication for cognitive effort discounting in the present study is that the decrease in choice of the hard lever following PCPA-treatment may be due primarily to impaired task performance. Previous work has found that serotonin depletion impaired performance in both novel object recognition and spontaneous alternation tasks (du Jardin et al, 2014;Pehrson et al, 2012). More so, short-term and spatial-working memory in rats is impaired by lesions of serotonergic neurons with the serotonin specific neurotoxin 5,7-DHT (Hritcu et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

Anabolic-androgenic steroids and cognitive effort discounting in male rats

Dokovna

Wood

2019

Hormones and Behavior

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Anabolic-androgenic steroids (AAS) are drugs of abuse that impair behavior and cognition. In a rodent model of AAS abuse, testosterone-treated male rats expend more physical effort, by repeatedly pressing a lever for a large reward in an operant discounting task. However, since modern society prioritizes cognitive over physical effort, it is important to determine if AAS limit cognitive effort. Here we tested the effects of AAS on a novel cognitive-effort discounting task. Each operant chamber had 3 nose-pokes, opposite 2 levers and a pellet dispenser. Rats pressed a lever to illuminate 1 nose-poke; they responded in the illuminated nose-poke to receive sugar pellets. For the 'easy' lever, the light remained on for 1s, and a correct response earned 1 pellet. For the 'hard' lever, the light duration decreased from 1s to 0.1s across 5 blocks of trials, and a correct response earned 4 pellets. As the duration of the nose-poke light decreased, all rats decreased their choice of the hard lever in a modest discounting curve. Task accuracy also decreased significantly across the 5 blocks of trials. However, there was no effect of testosterone on choice of the hard lever or task accuracy. Antagonism of dopamine D1 or D2 receptors had no effect on lever choice or task accuracy. However, serotonin depletion significantly decreased preference for the hard lever, and impaired task accuracy. Thus, physical effort discounting depends on dopamine activity, while cognitive effort discounting task is sensitive to serotonin. AAS impair physical effort discounting, but not cognitive effort discounting.

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P.2.d.003 The novel multimodal antidepressant Lu AA21004 improves memory performance in 5-HT depleted rats via 5-HT3 and 5-HT1A receptor mechanisms

Cited by 6 publications

References 0 publications

Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction

The serotonergic system and cognitive function

Anabolic-androgenic steroids and cognitive effort discounting in male rats

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