Prior stress history shapes adolescent alcohol-induced transcriptional changes in striatal glutamatergic and endocannabinoid pathways

Authors

  • 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

Keywords:

ALCOHOL, STRESS, ADOLESCENCE, STRIATUM, GLUTAMATERGIC, ENDOCANNABINOID

Abstract

Adolescence is a critical developmental window during which exposure to stress and alcohol can induce long-lasting neurobiological alterations. Binge-like alcohol consumption is particularly disruptive to corticostriatal circuits, but the extent to which prior stress history modulates these effects remains poorly understood. Here, we investigated how acute versus repeated restraint stress before intermittent alcohol exposure during adolescence shapes transcriptional changes in the dorsal striatum of male rats. Animals were exposed either to a single (acute) or five-day (repeated) restraint stress at postnatal day (PND) 32–36, followed by four weeks of intermittent intragastric ethanol (3 g/kg) or saline administration. At adult age, striatal mRNA expression of dopaminergic (Drd1, Drd2, Th), glutamatergic (Gls, Gls2, Gria2, Grin2a, Grin2b), endocannabinoid (Cnr1, Cnr2, Napepld, Faah, Dagla, Daglb, Mgll), neurotrophic (Bdnf, Ntrk2), and glial (Gfap, Aif1) genes was quantified. Alcohol exposure upregulated genes associated with glutamate synthesis and receptor signaling, endocannabinoid metabolism, and astrocytic activation. Acute stress amplified alcohol-induced expression of Gls, Gls2, Gria2, Napepld, Faah, Daglb, Ntrk2, and Gfap, while repeated stress blunted these effects and selectively enhanced Drd1, Drd2, Grin2a, and Bdnf expression. Microglial activation (Aif1) was increased by alcohol independently of stress. These results suggest that acute stress sensitizes glutamatergic and endocannabinoid pathways to alcohol, whereas repeated stress engages adaptive mechanisms consistent with the stress inoculation hypothesis. Overall, stress history critically determines the neurobiological outcomes of adolescent alcohol exposure, with implications for resilience and vulnerability to alcohol-induced psychopathology.

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2025-12-23

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Vol. 37 No. 4 (2025)

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Originals