Abstract
Rationale
Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability.
Objectives
After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective.
Results
We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective.
Conclusions
These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.
Graphical Abstract
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Data availability
The data supporting this study's findings are available from the corresponding author upon reasonable request.
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Acknowledgements
This study was supported by Brazilian grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 304851/2022-1) and FAPESP (2017/24304-0), which had no other role in the design of the study, collection, and analysis of data and decision to submit the paper for publication.
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This study was supported by Brazilian grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 304851/2022–1) and FAPESP (2017/24304–0), which had no other role in the design of the study, data collection and analysis, and decision to submit the paper for publication.
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L.A.S.: conceptualization, investigation, methodology, and draft writing; L.M.M.N.: investigation; F.S.G.: funding acquisition and draft writing; L.G.: conceptualization, supervision, and draft writing; and L.J.B.: conceptualization, data curation, formal analysis, funding acquisition, project administration, resources, supervision, and writing—review & editing.
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Francisco S. Guimarães is a co-inventor (Mechoulam R, JC, Guimaraes FS, AZ, JH, Breuer A) of the patent "Fluorinated CBD compounds, compositions and uses. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023" Def. US no. Reg. 62193296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to "develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease, and anxiety disorders". The other authors declare no competing interests.
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Chemical compounds used in this article: .
• Cannabidiol (PubChem CID: 644019).
• Clonidine (PubChem CID: 2803).
• D-cycloserine (PubChem CID: 6234).
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Soares, L.A., Nascimento, L.M.M., Guimarães, F.S. et al. Dual-step pharmacological intervention for traumatic-like memories: implications from D-cycloserine and cannabidiol or clonidine in male and female rats. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06596-8
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DOI: https://doi.org/10.1007/s00213-024-06596-8