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Brexpiprazole blocks post-traumatic stress disorder-like memory while promoting normal fear memory

Molecular Psychiatry volume 26, pages 3018–3033 (2021)Cite this article

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Abstract

A cardinal feature of post-traumatic stress disorder (PTSD) is a long-lasting paradoxical alteration of memory with hypermnesia for salient traumatic cues and amnesia for peri-traumatic contextual cues. So far, pharmacological therapeutic approach of this stress-related disorder is poorly developed mainly because of the lack of animal model for this paradoxical memory alteration. Using a model that precisely recapitulates the two memory components of PTSD in mice, we tested if brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, may persistently prevent the expression of PTSD-like memory induced by injection of corticosterone immediately after fear conditioning. Acute administration of brexpiprazole (0.3 mg/kg) 7 days’ post-trauma first blocks the expression of the maladaptive fear memory for a salient but irrelevant trauma-related cue. In addition, it enhances (with superior efficacy when compared to diazepam, prazosin, and escitalopram) memory for the traumatic context, correct predictor of the threat. This beneficial effect of brexpiprazole is overall maintained 1 week after treatment. In contrast brexpiprazole fully spares normal/adaptive cued fear memory, showing that the effect of this drug is specific to an abnormal/maladaptive (PTSD-like) fear memory of a salient cue. Finally, this treatment not only promotes the switch from PTSD-like to normal fear memory, but also normalizes most of the alterations in the hippocampal–amygdalar network activation associated with PTSD-like memory, as measured by C-Fos expression. Altogether, these preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.

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Fig. 1: Administration of brexpiprazole (BREX) prevents the expression of PTSD-like memory.
Fig. 2: Compared to three reference drugs, brexpiprazole is the only one that fully and persistently promotes normal fear memory after traumatic condition.
Fig. 3: Specific and persistent blockade of the abnormal (PTSD-like) fear response to the tone by brexpiprazole.
Fig. 4: Partial normalization of the hippocampal hypoactivation by brexpiprazole 1 week after treatment (day 14).
Fig. 5: Full normalization of the amygdalar hyperactivation by brexpiprazole 1 week after treatment (day 14).

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Acknowledgements

We thank all of the personnel of the Animal Facility of the Neurocentre Magendie for mouse care. This work was supported by H Lundbeck A/S, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Conseil Régional d’Aquitaine, Ministère de l’Enseignement supérieur et de la Recherche, University of Bordeaux.

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Author notes

  1. Pier-Vincenzo Piazza

    Present address: Aelis Farma, Neurocentre Magendie, F-33000, Bordeaux, France

  2. These authors jointly supervised this work: Aline Desmedt, Pier-Vincenzo Piazza

Authors and Affiliations

  1. INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, F-33000, Bordeaux, France

    Eva-Gunnel Ducourneau, Christelle Guette, Damien Perrot, Miguel Mondesir, Aline Desmedt & Pier-Vincenzo Piazza

  2. Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U1215, F-33000, Bordeaux, France

    Eva-Gunnel Ducourneau, Christelle Guette, Damien Perrot, Miguel Mondesir, Aline Desmedt & Pier-Vincenzo Piazza

  3. Synaptic Transmission In Vivo, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark

    Cédric Mombereau & Jorn Arnt

  4. Sunred Pharma Consulting ApS, Svend Gønges Vej 11A, DK-2680, Solrød Strand, Denmark

    Jorn Arnt

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Correspondence to Aline Desmedt.

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The authors declare no competing financial interests. CM is a Lundbeck employee and JA is a paid consultant for Lundbeck.

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Ducourneau, EG., Guette, C., Perrot, D. et al. Brexpiprazole blocks post-traumatic stress disorder-like memory while promoting normal fear memory. Mol Psychiatry 26, 3018–3033 (2021). https://doi.org/10.1038/s41380-020-0852-z

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