Efectos de los ácidos grasos omega-3 sobre la localización del receptor cannabinoide CB1 en la región CA1 del hipocampo tras la abstinencia de alcohol en ratones machos adolescentes

• Grandes, Pedro ; Serrano, Maitane ^[1] ; Lekunberri, Leire ^[1] ; Ocerin, Garazi ^[1] ; Saumell-Esnaola, Miquel ^[1] ; García del Caño, Gontzal ^[2] ; Puente, Nagore ^[1] ; Bonilla-Del Río, Itziar ^[1]
  1. [1] Universidad del País Vasco/Euskal Herriko Unibertsitatea

     Universidad del País Vasco/Euskal Herriko Unibertsitatea

     Leioa, España

     
  2. [2] Instituto de Salud Carlos III

     Instituto de Salud Carlos III

     Madrid, España

     
• Localización: Adicciones: Revista de socidrogalcohol, ISSN 0214-4840, Vol. 37, Nº. 4, 2025, págs. 341-352
• Idioma: español
• Títulos paralelos:
  • Effects of omega-3 fatty acids on CB1 cannabinoid receptor localization in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice
• Enlaces
  • Texto completo  1    2  
• Resumen
  • español

    El consumo excesivo de alcohol durante la adolescencia compromete la plasticidad sináptica y las funciones cognitivas, en parte debido a la interferencia con el sistema endocannabinoide (SEC) y su receptor CB1. Asimismo, el alcohol impacta negativamente en los ácidos grasos omega-3, esenciales para la integridad de las membranas celulares y la función cerebral. La deficiencia de omega-3 altera la señalización del SEC y la expresión y funcionalidad del CB1, exacerbando el deterioro inducido por el alcohol. Por el contrario, la activación del SEC contribuye a restaurar las funciones sinápticas dependientes de este sistema, afectadas por la falta de omega-3. De hecho, se ha demostrado que la suplementación con omega-3 normaliza la expresión del CB1 en regiones cerebrales específicas de ratones adultos expuestos al alcohol durante la adolescencia.

    A pesar de la estrecha relación entre alcohol, omega-3 y SEC, el efecto directo de los omega-3 sobre la localización subcelular del receptor CB1 tras la exposición al alcohol permanece poco explorado. Para abordar esta cuestión, analizamos la región CA1 del hipocampo en ratones machos adultos en abstinencia después de la ingesta de alcohol durante la adolescencia, utilizando inmunocitoquímica para microscopía electrónica. Nuestros resultados indican que los omega-3 ayudan a restablecer el equilibrio entre excitación e inhibición sináptica, alterado por un aumento en el número de terminales excitadoras y una reducción significativa de las inhibidoras. Sin embargo, ni la distribución ni la densidad del receptor CB1 en compartimentos neuronales y gliales se modificaron tras la exposición al alcohol ni con la suplementación con omega-3.

    Estos hallazgos revelan efectos estructurales novedosos de los omega-3 en la protección frente al daño cerebral inducido por el alcohol, aportando nuevas perspectivas sobre los mecanismos neuroprotectores de estos ácidos grasos.

  • English

    Adolescent binge drinking has detrimental effects on brain function, leading to long-lasting impairments in synaptic plasticity, cognition, and behavior. These effects are mediated, in part, by disruption of the endocannabinoid system (ECS) and its cannabinoid type-1 (CB1) receptor. Alcohol consumption also depletes omega-3 fatty acids, which are essential for maintaining cell membrane integrity and supporting brain function. This depletion impairs synaptic plasticity by disrupting endocannabinoid signaling and reducing CB1 receptor expression and function. Conversely, enhancement of the ECS can restore brain function and reverse the loss of endocannabinoid-dependent synaptic plasticity associated with omega-3 deficiency. Notably, omega-3 supplementation has been shown to restore CB1 receptor expression in specific brain regions in adult mice following adolescent alcohol exposure. However, despite the established interplay between alcohol, omega-3, and the ECS, the direct impact of omega-3 supplementation on the subcellular localization of CB1 receptors after alcohol exposure remains poorly understood.

    In this study, we used immunoelectron microscopy to investigate whether omega-3 supplementation influences CB1 receptor distribution in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice. Our results demonstrate that omega-3 partially restore the excitatory/inhibitory balance disrupted by alcohol, as evidenced by an increased number of excitatory terminals and a significant reduction in inhibitory terminals. However, the distribution and density of CB1 receptors within neuronal and glial compartments remain unchanged following alcohol exposure and omega-3 supplementation.

    These findings highlight novel structural effects of omega-3 in mitigating alcohol-induced brain damage.

• Referencias bibliográficas
  • Abrahao, K. P., Salinas, A. G. y Lovinger, D. M. (2017). Alcohol and the brain: neuronal molecular targets, synapses and circuits. Neuron,...
  • Achicallende, S., Bonilla-Del Río, I., Serrano, M., Mimenza, A., Lekunberri, L., Anaut-Lusar, I., Puente, N., Gerrikagoitia, I. y Grandes,...
  • Aguilera García, C., Navarro Alarcón, M., Alonso Aperte, E., Álvarez Mercado, A. I., Carvajales, P. A. y Arredondo Olguín, M. (2010). Tratado...
  • Akbar, M., Baick, J., Calderon, F., Wen, Z. y Kim, Y. (2006). Ethanol promotes neuronal apoptosis by inhibiting phosphatidylserine accumulation....
  • Arzua, T., Yan, Y., Liu, X., Dash, R. K., Liu, Q.-S. y Bai, X. (2024). Synaptic and mitochondrial mechanisms behind alcohol-induced imbalance...
  • Basavarajappa, B., Cooper, T. B. y Hungund, B. L. (1998). Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain...
  • Bazinet, R. P. y Layé, S. (2014). Polyunsaturated fatty acids and their metabolites in brain function and disease. Nature Reviews Neuroscience,...
  • Bondi, C., Taha, A., Tock, J., NK, T., CHeon, Y., Torres, G., Rapoport, R. y Moghaddam, B. (2014). Adolescent behavior and dopamine availability...
  • Bonilla-Del Rίo, I., Puente, N., Peñasco, S., Rico, I., Gutiérrez-Rodrίguez, A., Elezgarai, I., Ramos, A., Reguero, L., Gerrikagoitia, I.,...
  • Borgonetti, V., Vozella, V., Ware, T., Cruz, B., Bullard, R., Cravatt, B. F., Galeotti, N. y Roberto, M. (2024). Excessive alcohol intake...
  • Calder, P. C. (2016). Docosahexaenoic Acid. Annals of Nutrition and Metabolism, 69(1), 8–21. https://doi.org/10.1159/000448262
  • Cao, D., Kevala, K., Kim, J., Moon, H., Beom Jun, S., Lovinger, D. y Kim, H. (2009). Docosahexaenoic acid promotes hippocampal neuronal development...
  • Ceccarini, J., Hompes, T., Verhaeghen, A., Casteels, C., Peuskens, H., Bormans, G., Claes, S. y Van Laere, K. (2014). Changes in cerebral...
  • Champeil-Potokar, G., Hennebelle, M., Latour, A., Vancassel, S. y Denis, I. (2016). DHA prevents corticosterone-induced changes in astrocyte...
  • Cservenka, A. y Brumback, T. (2017). The burden of binge and heavy drinking on the brain: Effects on adolescent and young adult neural structure...
  • Das, M. y Das, S. (2019). Docosahexaenoic acid (DHA) induced morphological differentiation of astrocytes is associated with transcriptional...
  • Donovan, J. E. (2009). Estimated blood alcohol concentrations for child and adolescent drinking and their implications for screening instruments....
  • Farooqui, A. A. (2012). Lipid mediators and their metabolism in the brain. Springer. https://doi.org/10.1007/978-1-4419-9940-5
  • Feltham, B. A., Louis, X. L., Eskin, M. N. A. y Suh, M. (2020). Docosahexaenoic acid: outlining the therapeutic nutrient potential to combat...
  • García-Baos, A., Alegre-Zurano, L., Cantacorps, L., Martín-Sánchez, A. y Valverde, O. (2021). Role of cannabinoids in alcohol-induced neuroinflammation....
  • Gonzalez, S., Cascio, M. G., Fernandez-Ruiz, J., Fezza, F., Di Marzo, V. y Ramos, J. (2002). Changes in endocannabinoid contents in the brain...
  • Haidary, M., Ahmadi-Soleimani, S. M., Ghofraninezad, M., Azhdari-Zarmehri, H. y Beheshti, F. (2024). Omega-3 fatty acids supplementation prevents...
  • Hashimoto, M., Katakura, M., Tanabe, Y., Al Mamun, A., Inoue, T., Hossain, S., Arita, M. y Shido, O. (2015). N-3 fatty acids effectively improve...
  • Hirvonen, J., Zanotti-Fregonara, P., Umhau, J. C., George, D. T., Rallis-Frutos, D., Lyoo, C. H., Li, C. T., Hines, C. S., Sun, H., Terry,...
  • Jeong, Y., Huh, N., Lee, J., Yun, I., Lee, J., Lee, I. y Jung, M. (2018). Role of the hippocampal CA1 region in incremental value learning....
  • Joffre, C., Rey, C. y Layé, S. (2019). N-3 polyunsaturated fatty acids and the resolution of neuroinflammation. Frontiers in Pharmacology,...
  • Kang, E., Yun, B., Cha, J., Suk, H. y Shin, E. (2024). Neurodevelopmental imprints of sociomarkers in adolescent brain connectomes. Scientific...
  • Keshavan, M., Giedd, J., Lau, J., Lewis, D. y Paus, T. (2014). Changes in the adolescent brain and the pathophysiology of psychotic disorders....
  • Kim, H. Y. (2008). Biochemical and biological functions of docosahexaenoic acid in the nervous system: modulation by ethanol. Chemistry and...
  • Kim, H. Y. y Spector, A. (2018). N-Docosahexaenoylethanolamine: a neurotrophic and neuroprotective metabolite of docosahexaenoic acid. Molecular...
  • Kim, J., Carlson, M. E., Kuchel, G. A., Newman, J. W. y Watkins, B. A. (2016). Dietary DHA reduces downstream endocannabinoid and inflammatory...
  • Kunos, G. (2020). Interactions between alcohol and the endocannabinoid system. Alcoholism: Clinical and Experimental Research, 44(4), 790–805....
  • Lafourcade, M., Larrieu, T., Mato, S., Duffaud, A., Sepers, M., Matias, I., De Smedt-Peyrusse, V., Labrousse, V. F., Bretillon, L., Matute,...
  • Lovinger, D. M. y Abrahao, K. P. (2018). Synaptic plasticity mechanisms common to learning and alcohol use disorder. Learning and Memory,...
  • Lovinger, D. M. y Alvarez, V. (2017). Alcohol and basal ganglia circuitry: animal models. Neuropharmacology, 1(122), 46–55. https://doi.org/10.1016/j.neuropharm.2017.03.023
  • Lovinger, D. M. y Roberto, M. (2013). Synaptic effects induced by alcohol. Current Topics in Behavioral Neurosciences, 13, 31–86. https://doi.org/10.1007/7854_2011_143
  • Lu, H. y Mackie, K. (2021). Review of the endocannabinoid system. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 6(6), 607–615....
  • Maccioni, P., Colombo, G. y Carai, M. (2010). Blockade of the cannabinoid CB1 receptor and alcohol dependence: Preclinical evidence and preliminary...
  • Metna-Laurent, M. y Marsicano, G. (2015). Rising stars modulation of brain functions by astroglial type-1 cannabinoid receptors. GLIA, 63(3),...
  • Ministerio de Salud. (2025). Estudes 2025.
  • Navarrete, F., Garcia-Gutierrez, M. S., Gasparyan, A., Navarro, D., Lopez-Picon, F., Morcuende, A., Femenía, T. y Manzanares, J. (2022). Biomarkers...
  • Ortiz, S., Oliva, J. M., Pérez-Rial, S., Palomo, T. y Manzanares, J. (2004). Chronic ethanol consumption regulates cannabinoid CB1 receptor...
  • Patten, A., Brocardo, P. S. y Christie, B. R. (2013a). Omega-3 supplementation can restore glutathione levels and prevent oxidative damage...
  • Patten, A., Sickmann, H. M., Dyer, R. A., Innis, S. M. y Christie, B. R. (2013b). Omega-3 fatty acids can reverse the long-term deficits in...
  • Pava, M. y Woodward, J. (2012). A Review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence...
  • Peñasco, S., Rico-Barrio, I., Puente, N., Fontaine, C. J., Ramos, A., Reguero, L., Gerrikagoitia, I., Rodríguez de Fonseca, F., Barrondo,...
  • Puente, N., Reguero, L., Elezgarai, I., Canduela, M. J., Mendizabal-Zubiaga, J., Ramos-Uriarte, A., Fernández-Espejo, E. y Grandes, P. (2015)....
  • Rhodes, J. S., Best, K., Belknap, J. K., Finn, D. A. y Crabbe, J. C. (2005). Evaluation of a simple model of ethanol drinking to intoxication...
  • Rico-Barrio, I., Peñasco, S., Lekunberri, L., Serrano, M., Egaña-Huguet, J., Mimenza, A., Soria-Gomez, E., Ramos, A., Buceta, I., Gerrikagoitia,...
  • Rico-Barrio, I., Peñasco, S., Puente, N., Ramos, A., Fontaine, C. J., Reguero, L., Giordano, M. E., Buceta, I., Terradillos, I., Lekunberri,...
  • Risher, M. L., Fleming, R. L., Risher, C., Miller, K., Klein, R., Wills, T., Acheson, S., Moore, S., Wilson, W., Eroglu, C. y Swartzwelder,...
  • Sabeti, J. (2011). Ethanol exposure in early adolescence inhibits intrinsic neuronal plasticity via sigma-1 receptor activation in hippocampal...
  • Sanchez-Marin, L., Flores-Lopez, M., Pastor, A., Gavito, A., Suarez, J., De la Torre, R., Pavón, F., Rodriguez de Fonseca, F. y Serrano, A....
  • Sanz-Martos, A. B., Fuentes-Verdugo, E., Merino, B., Morales, L., Pérez, V., Capellán, R., Pellón, R., Miguéns, M. y del Olmo, N. (2023)....
  • Serrano, A., Pavon, F., Buczynsky, M., Schlosburg, J., Natividad, L. A., Polis, I., Stouffer, D., Zorrilla, E., Roberto, M., Cravatt, B.,...
  • Serrano, A., Rivera, P., Pavon, F., Decara, J., Suarez, J., Rodriguez de Fonseca, F. y Parsons, L. (2012). Differential effects of single...
  • Serrano, M., Rico-Barrio, I. y Grandes, P. (2023). The effect of omega-3 fatty acids on alcohol-induced damage. Frontiers in Nutrition, 10,...
  • Serrano, M., Saumell-Esnaola, M., Ocerin, G., García del Caño, G., Puente, N., Sallés, J., Rodriguez de Fonseca, F., Rodriguez Arias, M.,...
  • Serrano, M., Saumell-Esnaola, M., Ocerin, G., García del Caño, G., Soria-Gómez, E., Mimenza, A., Puente, N., Bonilla-Del Rίo, I., Ramos-Uriarte,...
  • Spear, L. P. (2018). Effects of adolescent alcohol consumption on the brain and behaviour. Nature Reviews Neuroscience, 19(4), 197–214. https://doi.org/10.1038/nrn.2018.10
  • Stopponi, S., Fotio, Y., Domi, A., Borruto, A., Natividad, L., Roberto, M., Ciccocioppo, R. y Cannella, N. (2018). Inhibition of fatty acid...
  • Takamiya, S., Shiotani, K., Ohnuki, T., Osako, Y., Tanisumi, Y., Yuki, S., Manabe, H., Hirokawa, J. y Sakurai, Y. (2021). Hippocampal CA1...
  • Vetreno, R. P. y Crews, F. T. (2015). Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and...
  • Vinod, K. Y., Yalamanchili, R., Xie, S., Cooper, T. B. y Hungund, B. L. (2006). Effect of chronic ethanol exposure and its withdrawal on the...
  • Wolfe, S., Vozella, V. y Roberto, M. (2022). The synaptic interactions of alcohol and the endogenous cannabinoid system. Alcohol Research,...