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Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats

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Abstract

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC.

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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Acknowledgements

We would like to thank Mr. Sjoerd Schurer from Noldus Technical Support for his prompt assistance and help in recovering damaged files from the MWM experiment.

Funding

This work was supported by the following funding sources: MCIN/AEI/10.13039/501100011033/ grant number PGC2018-099117-B-C21 Gobierno de España, UAL2020- CTSD2068 with FEDER I+D+I funds “Una manera de hacer Europa,” PND-2022l024 Plan Nacional sobre Drogas, Ministerio de Sanidad, Gobierno de España and PID2022-139286NB-I00 Proyectos de Generación de Conocimiento 2022, Gobierno de España.

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Authors and Affiliations

  1. Department of Psychology and Health Research Center CEINSA, University of Almería, Ctra. Sacramento, s/n, 04120, Almería, Spain

    Ángeles Prados-Pardo, Elena Martín-González, Carlos Martín, Manuela Olmedo-Córdoba, Cristian Pérez-Fernandez, Fernando Sánchez-Santed & Margarita Moreno-Montoya

  2. Department of Neuroscience and Panum Institute, University of Copenhagen, Copenhagen, Denmark

    Santiago Mora

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  1. Ángeles Prados-Pardo
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  2. Elena Martín-González
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  3. Santiago Mora
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  4. Carlos Martín
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  8. Margarita Moreno-Montoya
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Contributions

ÁPP and MM contributed to the conception and design of the study. ÁPP, EMG, SM, CM, and MOC collected and analyzed the data. CPF contributed with methodological assistance. FSS contributed to the data interpretation. ÁPP wrote the first draft of the manuscript. MM supervised all the experimental processes. MM also had contributions with the resources, the project administration, and the funding acquisition. All authors contributed to the manuscript revision, and read, and approved the submitted version.

Corresponding author

Correspondence to Margarita Moreno-Montoya.

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Ethics Approval

All procedures were carried out following the Spanish Royal Decree 53/ 2013 on the protection of experimental animals, the European Community Directive 2010/63/EU for animal experiments, and comply with the ARRIVE guidelines for animal research. The Animal Research Committee of the University of Almeria approved the experiments described here, and the authors declare that the research shows commitment to the 3Rs principle (replacement, reduction, refinement).

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Prados-Pardo, Á., Martín-González, E., Mora, S. et al. Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats. Mol Neurobiol 60, 6975–6991 (2023). https://doi.org/10.1007/s12035-023-03506-5

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