El historial previo de estrés modula los cambios transcripcionales inducidos por alcohol en la adolescencia en las vías glutamatérgicas y endocannabinoides del estriado

Autores/as

  • Laura Sanchez-Marin
  • Berke Canoluk Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590, Málaga, Spain ** Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain
  • Julia Verheul-Campos Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590, Málaga, Spain ** Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain
  • Ana Gavito Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590, Málaga, Spain ** Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain
  • Javier Pavon Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590, Málaga, Spain Área del Corazón, Hospital Universitario Virgen de la Victoria, Málaga, Spain
  • Antonia Serrano Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590, Málaga, Spain ** Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain
  • Fernando Rodríguez de Fonseca IMABIS. Hospital Carlos Haya, Málaga
  • Raquel Reviriego Hospital Regional Universitario de Málaga

Palabras clave:

Alcohol, Estrés, Adolescencia, Estriado, Glutamato, Endocannabinoide

Resumen

La adolescencia es una etapa de desarrollo crítica durante la cual la exposición al estrés y al alcohol puede inducir alteraciones neurobiológicas de larga duración. El consumo de alcohol en atracón es especialmente disruptivo para los circuitos corticoestriatales, sin embargo, aún se conoce poco sobre hasta qué punto la historia previa de estrés modula estos efectos. En este estudio investigamos cómo el estrés por inmovilización, ya sea agudo o repetido, antes de la exposición intermitente al alcohol durante la adolescencia modula los cambios transcripcionales en el estriado dorsal de ratas macho. Los animales fueron expuestos a una sesión única (agudo) o a cinco días consecutivos (repetido) de estrés por inmovilización entre los días posnatales (DPN) 32–36, seguido de cuatro semanas de administración intermitente intragástrica de etanol (3 g/kg) o solución salina. En la edad adulta se cuantificó la expresión de ARNm estriatal de genes dopaminérgicos (Drd1, Drd2, Th), glutamatérgicos (Gls, Gls2, Gria2, Grin2a, Grin2b), endocannabinoides (Cnr1, Cnr2, Napepld, Faah, Dagla, Daglb, Mgll), neurotróficos (Bdnf, Ntrk2) y gliales (Gfap, Aif1). La exposición al alcohol incrementó la expresión de genes asociados con la síntesis de glutamato y la señalización de receptores, el metabolismo endocannabinoide y la activación astrocítica. El estrés agudo amplificó la expresión inducida por alcohol de Gls, Gls2, Gria2, Napepld, Faah, Daglb, Ntrk2 y Gfap, mientras que el estrés repetido atenuó estos efectos y aumentó selectivamente la expresión de Drd1, Drd2, Grin2a y Bdnf. La activación microglial (Aif1) se incrementó por el alcohol independientemente del estrés. Estos resultados sugieren que el estrés agudo sensibiliza las vías glutamatérgicas y endocannabinoides al alcohol, mientras que el estrés repetido activa mecanismos adaptativos consistentes con la hipótesis de la inoculación de estrés. En conjunto, el historial de estrés determina de manera crítica los resultados neurobiológicos de la exposición al alcohol durante la adolescencia, con implicaciones para la resiliencia y la vulnerabilidad a la psicopatología inducida por alcohol.

Citas

Abrahao, K. P., Salinas, A. G. y Lovinger, D. M. (2017). Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits. Neuron, 96(6), 1223-1238. https://doi.org/10.1016/j.neuron.2017.10.032

Alfonso-Loeches, S., Pascual-Lucas, M., Blanco, A. M., Sanchez-Vera, I. y Guerri, C. (2010). Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci, 30(24), 8285-8295. https://doi.org/10.1523/JNEUROSCI.0976-10.2010

Baik, J. H. (2020). Stress and the dopaminergic reward system. Exp Mol Med, 52(12), 1879-1890. https://doi.org/10.1038/s12276-020-00532-4

Binder, D. K. y Scharfman, H. E. (2004). Brain-derived neurotrophic factor. Growth Factors, 22(3), 123-131. https://doi.org/10.1080/08977190410001723308

Boutros, N., Der-Avakian, A., Kesby, J. P., Lee, S., Markou, A. y Semenova, S. (2018). Effects of adolescent alcohol exposure on stress-induced reward deficits, brain CRF, monoamines and glutamate in adult rats. Psychopharmacology (Berl), 235(3), 737-747. https://doi.org/10.1007/s00213-017-4789-0

Carrara-Nascimento, P. F., Griffin, W. C., 3rd, Pastrello, D. M., Olive, M. F. y Camarini, R. (2011). Changes in extracellular levels of glutamate in the nucleus accumbens after ethanol-induced behavioral sensitization in adolescent and adult mice. Alcohol, 45(5), 451-460. https://doi.org/10.1016/j.alcohol.2011.01.002

Carrara-Nascimento, P. F., Hoffmann, L. B., Florio, J. C., Planeta, C. S. y Camarini, R. (2020). Effects of Ethanol Exposure During Adolescence or Adulthood on Locomotor Sensitization and Dopamine Levels in the Reward System. Front Behav Neurosci, 14, 31. https://doi.org/10.3389/fnbeh.2020.00031

Caudal, D., Godsil, B. P., Mailliet, F., Bergerot, D. y Jay, T. M. (2010). Acute stress induces contrasting changes in AMPA receptor subunit phosphorylation within the prefrontal cortex, amygdala and hippocampus. PLoS One, 5(12), e15282. https://doi.org/10.1371/journal.pone.0015282

Chaby, L. E., Sadik, N., Burson, N. A., Lloyd, S., O’Donnel, K., Winters, J.,…Perrine, S. A. (2020). Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats. Sci Rep, 10(1), 17935. https://doi.org/10.1038/s41598-020-74481-3

Cheng, Y., Wang, X., Wei, X., Xie, X., Melo, S., Miranda, R. C. y Wang, J. (2018). Prenatal Exposure to Alcohol Induces Functional and Structural Plasticity in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum. Alcohol Clin Exp Res. https://doi.org/10.1111/acer.13806

Clabough, E., Ingersoll, J., Reekes, T., Gleichsner, A. y Ryan, A. (2021). Acute Ethanol Exposure during Synaptogenesis Rapidly Alters Medium Spiny Neuron Morphology and Synaptic Protein Expression in the Dorsal Striatum. Int J Mol Sci, 23(1). https://doi.org/10.3390/ijms23010290

Dannenhoffer, C. A., Gomez, A. A., Macht, V. A., Jawad, R., Sutherland, E. B., Vetreno, R. P.,…Robinson, D. L. (2022). Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood. Alcohol Clin Exp Res, 46(5), 759-769. https://doi.org/10.1111/acer.14810

Favoretto, C. A., Bertagna, N. B., Anjos-Santos, A., Loss, C. M., Rodolpho, B. T., Righi, T.,…Cruz, F. C. (2025). Impacts of maternal separation stress on ethanol intake and endocannabinoid system in adolescent mice. Neuroscience, 565, 124-137. https://doi.org/10.1016/j.neuroscience.2024.11.037

Franklin, T. B., Saab, B. J. y Mansuy, I. M. (2012). Neural mechanisms of stress resilience and vulnerability. Neuron, 75(5), 747-761. https://doi.org/10.1016/j.neuron.2012.08.016

Galaj, E., Kipp, B. T., Floresco, S. B. y Savage, L. M. (2019). Persistent Alterations of Accumbal Cholinergic Interneurons and Cognitive Dysfunction after Adolescent Intermittent Ethanol Exposure. Neuroscience, 404, 153-164. https://doi.org/10.1016/j.neuroscience.2019.01.062

Gass, J. T., Glen, W. B., Jr., McGonigal, J. T., Trantham-Davidson, H., Lopez, M. F., Randall, P. K.,…Chandler, L. J. (2014). Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood. Neuropsychopharmacology, 39(11), 2570-2583. https://doi.org/10.1038/npp.2014.109

Hauser, S. R., Mulholland, P. J., Truitt, W. A., Waeiss, R. A., Engleman, E. A., Bell, R. L. y Rodd, Z. A. (2021). Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell. Int J Mol Sci, 22(21). https://doi.org/10.3390/ijms222111733

Hoops, D. y Flores, C. (2017). Making Dopamine Connections in Adolescence. Trends Neurosci, 40(12), 709-719. https://doi.org/10.1016/j.tins.2017.09.004

Huntley, E. D., Marusak, H. A., Berman, S. E., Zundel, C. G., Hatfield, J. R. B., Keating, D. P. y Rabinak, C. A. (2020). Adolescent substance use and functional connectivity between the ventral striatum and hippocampus. Behav Brain Res, 390, 112678. https://doi.org/10.1016/j.bbr.2020.112678

Johnson, K. A., Liput, D. J., Homanics, G. E. y Lovinger, D. M. (2020). Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse striatum by chronic ethanol exposure. Alcohol, 82, 11-21. https://doi.org/10.1016/j.alcohol.2019.06.003

Juliano, V. A. L., Albernaz-Mariano, K. A., Covre, L. H. H., Juca, P. M., Pereira, R. M., Shigeo-de-Almeida, A.,…Munhoz, C. D. (2025). Neurobiological intersections of stress and substance use disorders. Front Neurosci, 19, 1548372. https://doi.org/10.3389/fnins.2025.1548372

Katona, I. y Freund, T. F. (2012). Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci, 35, 529-558. https://doi.org/10.1146/annurev-neuro-062111-150420

Logrip, M. L., Barak, S., Warnault, V. y Ron, D. (2015). Corticostriatal BDNF and alcohol addiction. Brain Res, 1628(Pt A), 60-67. https://doi.org/10.1016/j.brainres.2015.03.025

Lotan, A., Lifschytz, T., Wolf, G., Keller, S., Ben-Ari, H., Tatarsky, P.,…Lerer, B. (2018). Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates. Mol Psychiatry, 23(6), 1432-1445. https://doi.org/10.1038/mp.2017.237

Lovinger, D. M. y Mathur, B. N. (2012). Endocannabinoids in striatal plasticity. Parkinsonism Relat Disord, 18 Suppl 1(Suppl 1), S132-134. https://doi.org/10.1016/S1353-8020(11)70041-4

Lyons, D. M. y Parker, K. J. (2007). Stress inoculation-induced indications of resilience in monkeys. J Trauma Stress, 20(4), 423-433. https://doi.org/10.1002/jts.20265

Morena, M., Aukema, R. J., Leitl, K. D., Rashid, A. J., Vecchiarelli, H. A., Josselyn, S. A. y Hill, M. N. (2019). Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety. J Neurosci, 39(7), 1275-1292. https://doi.org/10.1523/JNEUROSCI.2251-18.2018

Morena, M., Patel, S., Bains, J. S. y Hill, M. N. (2016). Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology, 41(1), 80-102. https://doi.org/10.1038/npp.2015.166

Morris, L. S., Dowell, N. G., Cercignani, M., Harrison, N. A. y Voon, V. (2018). Binge drinking differentially affects cortical and subcortical microstructure. Addict Biol, 23(1), 403-411. https://doi.org/10.1111/adb.12493

Murakami, S., Imbe, H., Morikawa, Y., Kubo, C. y Senba, E. (2005). Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res, 53(2), 129-139. https://doi.org/10.1016/j.neures.2005.06.008

O’Tousa, D. y Grahame, N. (2014). Habit formation: implications for alcoholism research. Alcohol, 48(4), 327-335. https://doi.org/10.1016/j.alcohol.2014.02.004

Pascual, M., Boix, J., Felipo, V. y Guerri, C. (2009). Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem, 108(4), 920-931. https://doi.org/10.1111/j.1471-4159.2008.05835.x

Paxinos, G. y Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates. New York: Academic Press, Spiral Bound.

Popoli, M., Yan, Z., McEwen, B. S. y Sanacora, G. (2011). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci, 13(1), 22-37. https://doi.org/10.1038/nrn3138

Portero-Tresserra, M., Gracia-Rubio, I., Cantacorps, L., Pozo, O. J., Gomez-Gomez, A., Pastor, A.,…Valverde, O. (2018). Maternal separation increases alcohol-drinking behaviour and reduces endocannabinoid levels in the mouse striatum and prefrontal cortex. Eur Neuropsychopharmacol, 28(4), 499-512. https://doi.org/10.1016/j.euroneuro.2018.02.003

Reguilon, M. D., Ferrer-Perez, C., Manzanedo, C., Minarro, J. y Rodriguez-Arias, M. (2025). Voluntary wheel running during adolescence prevents the increase in ethanol intake induced by social defeat in male mice. Psychopharmacology (Berl), 242(5), 979-996. https://doi.org/10.1007/s00213-023-06461-0

Salinas, A. G., Nadel, J. A., Mateo, Y., Huynh, T., Augustin, S. M., Pacak, K. y Lovinger, D. M. (2022). Chronic Ethanol Consumption Alters Presynaptic Regulation of Dorsal Striatal Dopamine Release in C57BL/6J Mice. Int J Mol Sci, 23(19). https://doi.org/10.3390/ijms231910994

Sanchez-Marin, L., Flores-Lopez, M., Gavito, A. L., Suarez, J., Pavon-Moron, F. J., de Fonseca, F. R. y Serrano, A. (2022a). Repeated Restraint Stress and Binge Alcohol during Adolescence Induce Long-Term Effects on Anxiety-like Behavior and the Expression of the Endocannabinoid System in Male Rats. Biomedicines, 10(3). https://doi.org/10.3390/biomedicines10030593

Sanchez-Marin, L., Flores-Lopez, M., Pastor, A., Gavito, A. L., Suarez, J., de la Torre, R.,…Serrano, A. (2022b). Acute stress and alcohol exposure during adolescence result in an anxious phenotype in adulthood: Role of altered glutamate/endocannabinoid transmission mechanisms. Prog Neuropsychopharmacol Biol Psychiatry, 113, 110460. https://doi.org/10.1016/j.pnpbp.2021.110460

Sanchez-Marin, L., Gavito, A. L., Decara, J., Pastor, A., Castilla-Ortega, E., Suarez, J.,…Serrano, A. (2020). Impact of intermittent voluntary ethanol consumption during adolescence on the expression of endocannabinoid system and neuroinflammatory mediators. Eur Neuropsychopharmacol, 33, 126-138. https://doi.org/10.1016/j.euroneuro.2020.01.012

Sanchez-Marin, L., Pavon, F. J., Decara, J., Suarez, J., Gavito, A., Castilla-Ortega, E.,…Serrano, A. (2017). Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation. Front Behav Neurosci, 11, 15. https://doi.org/10.3389/fnbeh.2017.00015

Sandi, C. y Pinelo-Nava, M. T. (2007). Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast, 2007, 78970. https://doi.org/10.1155/2007/78970

Shnitko, T. A., Spear, L. P. y Robinson, D. L. (2016). Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats. Psychopharmacology (Berl), 233(3), 361-371. https://doi.org/10.1007/s00213-015-4106-8

Sircar, R. (2020). Repeated unpredictable stress blunts alcohol-induced memory deficit in adolescent rat. Neuroreport, 31(15), 1090-1095. https://doi.org/10.1097/WNR.0000000000001519

Van Waes, V., Darnaudery, M., Marrocco, J., Gruber, S. H., Talavera, E., Mairesse, J.,…Morley-Fletcher, S. (2011). Impact of early life stress on alcohol consumption and on the short- and long-term responses to alcohol in adolescent female rats. Behav Brain Res, 221(1), 43-49. https://doi.org/10.1016/j.bbr.2011.02.033

Verheul-Campos, J., Sanchez-Marin, L., Lopez, Y., Gavito, A. L., Grandes, P., Serrano, P.,…de Fonseca, F. R. (2025). Prior restraint stress counteracts memory deficits associated with adolescent alcohol exposure by targeting both the hippocampal endocannabinoid and glutamatergic systems. Drug Alcohol Depend, 276, 112891. https://doi.org/10.1016/j.drugalcdep.2025.112891

Vrettou, M., Granholm, L., Todkar, A., Nilsson, K. W., Wallen-Mackenzie, A., Nylander, I. y Comasco, E. (2017). Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress. Addict Biol, 22(2), 369-380. https://doi.org/10.1111/adb.12331

Wilcox, M. V., Cuzon Carlson, V. C., Sherazee, N., Sprow, G. M., Bock, R., Thiele, T. E.,…Alvarez, V. A. (2014). Repeated binge-like ethanol drinking alters ethanol drinking patterns and depresses striatal GABAergic transmission. Neuropsychopharmacology, 39(3), 579-594. https://doi.org/10.1038/npp.2013.230

Yuen, E. Y., Liu, W., Karatsoreos, I. N., Feng, J., McEwen, B. S. y Yan, Z. (2009). Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci U S A, 106(33), 14075-14079. https://doi.org/10.1073/pnas.0906791106

Zandy, S. L., Matthews, D. B., Tokunaga, S., Miller, A., Blaha, C. D. y Mittleman, G. (2015). Reduced dopamine release in the nucleus accumbens core of adult rats following adolescent binge alcohol exposure: age and dose-dependent analysis. Psychopharmacology (Berl), 232(4), 777-784. https://doi.org/10.1007/s00213-014-3712-1

Zou, S. y Kumar, U. (2018). Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci, 19(3). https://doi.org/10.3390/ijms19030833

Descargas

Publicado

2025-12-23

Número

Vol. 37 Núm. 4 (2025)

Sección

Originales