{
  "abstract": "Background: Nicotine dependence is characterized by high relapse rates, often complicated by comorbid alcohol consumption. Both substances dysregulate glutamatergic signaling and promote oxidative stress in the nucleus accumbens (NAc), mechanisms that may contribute to persistent drug seeking. This study evaluated the therapeutic potential of Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2 (ALDH2), to reduce nicotine and concurrent ethanol/nicotine intake, post-deprivation reaccess, and examined its association with accumbal glutamate homeostasis.\n\nMethods: Female alcohol-preferring UChB rats were induced to voluntarily consume nicotine or a combination of nicotine and ethanol. Rats received Alda-1 (25 mg/kg, p. o.) or vehicle during chronic maintenance and during a 14-day deprivation period. Extracellular glutamate levels in NAc were assessed by, and GLT-1 levels were determined by Western blot.\n\nResults: Alda-1 administration significantly suppressed chronic nicotine intake by 67% and reduced post-deprivation nicotine consumption by 82%. These behavioral changes were accompanied by a 40% reduction in extracellular glutamate levels in the NAc, restoring them to baseline levels observed in naïve controls. In the co-consumption model, Alda-1 effectively reduced chronic ethanol and nicotine intake by 80%–90%. However, Alda-1 failed to reduce post-deprivation intake in the dual-substance paradigm. This lack of efficacy was accompanied by GLT-1 downregulation induced by concurrent ethanol/nicotine exposure, which was not reversed by Alda-1.\n\nConclusion: Our findings indicate that ALDH2 activation by Alda-1 markedly reduced chronic and post-deprivation nicotine intake, an effect associated with improved glutamate homeostasis. Alda-1 also attenuates chronic polysubstance use; however, its efficacy is lost during post-deprivation re-access in the co-consumption model associated with GLT-1 downregulation, suggesting synergistic neuroadaptations may bypass ALDH2-mediated pathways.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile",
    "Transdisciplinary Nucleus of Pharmacology and Immunology, ICBM, Faculty of Medicine, University of Chile",
    "Department of Neuroscience, Faculty of Medicine, University of Chile",
    "Specialized Center for Prevention of Substance Use and Treatment of Addictions (CESA), University of Chile"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Fresia Solís-Egaña"
    },
    {
      "affs": [
        0
      ],
      "name": "Sofía Adasme-Reyes"
    },
    {
      "affs": [
        0
      ],
      "name": "Ignacio Gutiérrez-Vega"
    },
    {
      "affs": [
        0
      ],
      "name": "María Elena Quilaqueo"
    },
    {
      "affs": [
        1
      ],
      "name": "María Elena Quintanilla"
    },
    {
      "affs": [
        0
      ],
      "name": "David Vásquez"
    },
    {
      "affs": [
        1
      ],
      "name": "Mario Herrera-Marschitz"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Paola Morales Retamales"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Mario Rivera-Meza"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/emzrnv3vma1r8.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1880813",
  "fulltext_url": "https://europepmc.org/articles/PMC13710817",
  "id": "emzrnv3vma1r8",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1880813/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2737|Smoking Behavior and Cessation"
    ]
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  "openalex": "W7221720468",
  "pdf_url": "https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1880813/pdf",
  "pmcid": "PMC13710817",
  "pmid": "42947951",
  "published": "2026-10-13",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/emzrnv3vma1r8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1880813",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1880813/full"
    },
    {
      "first_seen": "2026-10-31T00:20:34Z",
      "native_id": "MED:42947951",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42947951"
    },
    {
      "first_seen": "2026-10-31T12:21:42Z",
      "native_id": "PMC13710817",
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      "url": "https://doi.org/10.3389/fphar.2026.1880813"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Smoking Behavior and Cessation",
      "subfield": "physiology"
    }
  ],
  "title": "Alda-1 reduces chronic and post-deprivation nicotine intake in rats: impact of concurrent ethanol consumption on treatment efficacy",
  "title_text": "Alda-1 reduces chronic and post-deprivation nicotine intake in rats: impact of concurrent ethanol consumption on treatment efficacy",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:42Z",
  "url": "https://research.draconitic.com/paper/emzrnv3vma1r8",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}