The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

Brabant, Christian; Charlier, Yana; Tirelli, Ezio

doi:10.1016/j.bbr.2012.12.063

Cited by 35 publications

(19 citation statements)

References 42 publications

(72 reference statements)

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“…Therefore, while context reexposure led to behaviorally defined extinction for all durations, this extinction was apparently NMDA receptor-dependent only for the 30-min condition. Moreover, the reconsolidation impairment with the brief reexposure duration was observed in spite of a significant between-session decline in freezing, as has been previously documented in the literature (Charlier and Tirelli 2011;Brabant et al 2013;Heath et al 2015). Importantly, we observed a similar pattern of freezing reduction even in the animals that received MK-801 after context reexposure, no matter how long the session lasted for (Fig.…”

Section: Discussionsupporting

confidence: 87%

On the transition from reconsolidation to extinction of contextual fear memories

et al. 2017

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Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3-and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor-independent decreases in freezing can still occur in these conditions.[Supplemental material is available for this article.]The retrieval of an associative memory can result in different outcomes. Retrieval in the absence of further reinforcement can destabilize a memory, requiring a process of reconsolidation (Nader and Hardt 2009), or can cause memory extinction through new inhibitory learning (Giustino and Maren 2015). The balance between destabilization and extinction appears to be influenced by the relative strength of learning and extent of nonreinforced retrieval (Eisenberg et al. 2003;Suzuki et al. 2004;Lee et al. 2006;de la Fuente et al. 2011;Flavell and Lee 2013). More extensive stimulus reexposure (i.e., extinction training), or weaker initial conditioning is more likely to result in extinction, whereas more restricted stimulus reexposure preferentially engages memory destabilization. This apparent competition between destabilization and extinction manifests as a bidirectional effect of amnestic treatment, depending of the parameters of conditioning and retrieval. Either reconsolidation is impaired to reduce subsequent memory expression, or extinction is disrupted to maintain expression of the original memory (Eisenberg et al. 2003;Suzuki et al. 2004;Lee et al. 2006;de la Fuente et al. 2011;Flavell and Lee 2013).In both appetitive Pavlovian and conditioned fear memories, recent evidence has indicated that extinction per se does not prevent memory destabilization and reconsolidation. In cue-sucrose, cue-fear, and context-fear settings, there appears to be a reexposure period between the parameters that engage destabilization and extinction, in which there is no behavioral effect of amnestic treatment (Flavell and Lee 2013;Merlo et al. 2014;Alfei et al. 2015). This "limbo" or "null poin...

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Section: Discussionsupporting

confidence: 87%

On the transition from reconsolidation to extinction of contextual fear memories

et al. 2017

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“…For example, Hrh3 −/− mice were resistant against the amnesic effect of scopolamine in the passive avoidance test (Toyota et al, 2002) and they showed improved spatial learning and memory in the Barnes maze (Rizk et al, 2004). Moreover, the H 3 R inverse agonist pitolisant exhibited memory-enhancing effects in the fear conditioning task with C57Bl/6J mice and ameliorated memory deficits that were induced by the NMDA antagonist dizolcilpine (Brabant et al, 2013).…”

Section: Alzheimer's Disease (Ad) and Vascular Dementiasmentioning

confidence: 97%

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

Schneider

Neumann

Seifert

2014

Neuroscience & Biobehavioral Reviews

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“…Thus, the available experimental data do not suggest any evident risk of abuse potential, but it could not be excluded. Furthermore, since pitolisant was found to enhance memory performance and the duration of acquisition in animal studies, diversion of pitolisant to improve intellectual performance has been considered as a potential risk in humans 40,41…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Romigi

Vitrani

Giudice

et al. 2018

DDDT

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Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and rapid eye movement sleep dysregulation, manifesting as cataplexy and sleep paralysis, as well as hypnagogic and hypnopompic hallucinations. Disease onset may occur at any age, although adolescents and young adults are mainly affected. Currently, the diagnosis delay ranges from 8 to 10 years and drug therapy may only attenuate symptoms. Pitolisant is a first-in-class new drug currently authorized by the European Medicines Agency to treat narcolepsy with or without cataplexy in adults and with an expanded evaluation for the treatment of neurologic diseases such as Parkinson’s disease and epilepsy. This article reviews the pharmacokinetic and pharmacodynamic profile of pitolisant, highlighting its effectiveness and safety in patients with narcolepsy. We performed a systematic review of the literature using PubMed, Embase, and Google Scholar. We report on the efficacy and safety data of pitolisant in narcoleptic patients regarding cataplexy episodes and subjective and objective daytime sleepiness. The development program of pitolisant was characterized by eight Phase II/III studies. One proof-of-concept study followed by two pivotal studies, three randomized controlled trials, and two open studies were evaluated. Our review confirmed the effectiveness of pitolisant in treating major clinically relevant narcolepsy symptoms, including cataplexy, as compared to placebo. In addition, pitolisant revealed a safe profile when compared with placebo and active comparators. Headache, insomnia, and nausea were the prominent side effects. Further long-term randomized controlled trials comparing the efficacy of pitolisant with active comparators (ie, modafinil and sodium oxybate) may clarify its real place in therapy and its possible use as a first-line agent on the basis of its safety and tolerability.

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The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

Cited by 35 publications

References 42 publications

On the transition from reconsolidation to extinction of contextual fear memories

On the transition from reconsolidation to extinction of contextual fear memories

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

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