Alda-1 reduces chronic and post-deprivation nicotine intake in rats: impact of concurrent ethanol consumption on treatment efficacy
4 affiliations
- 1Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, University of Chile
- 2Transdisciplinary Nucleus of Pharmacology and Immunology, ICBM, Faculty of Medicine, University of Chile
- 3Department of Neuroscience, Faculty of Medicine, University of Chile
- 4Specialized Center for Prevention of Substance Use and Treatment of Addictions (CESA), University of Chile
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.
Methods: 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.
Results: 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.
Conclusion: 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.
Related
- A Systematic Review and Meta-Analysis: Does Molecular Hydrogen Exert Radioprotective Effects Without Compromising the Antitumor Efficacy of Radiotherapy or Concurrent Chemoradiotherapy?
- Socioeconomic and demographic patterning of concurrent tobacco smoking and alcohol consumption among men in Malawi: evidence from the 2024 Malawi demographic and health survey
- Clinical efficacy and safety of immunotherapy after concurrent chemoradiotherapy in advanced esophageal cancer.
- Efficacy and safety analysis of consolidation immunotherapy following definitive concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma
- International best practice in the cessation of vaping and non-combustible nicotine use, and barriers, facilitators and treatment preferences: A rapid review
BibTeX
@article{solisegana2026alda1,
title = {{Alda-1 reduces chronic and post-deprivation nicotine intake in rats: impact of concurrent ethanol consumption on treatment efficacy}},
author = {Fresia Solís-Egaña and Sofía Adasme-Reyes and Ignacio Gutiérrez-Vega and María Elena Quilaqueo and María Elena Quintanilla and David Vásquez and Mario Herrera-Marschitz and Paola Morales Retamales and Mario Rivera-Meza},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1880813},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1880813/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Alda-1 reduces chronic and post-deprivation nicotine intake in rats: impact of concurrent ethanol consumption on treatment efficacy
AU - Fresia Solís-Egaña
AU - Sofía Adasme-Reyes
AU - Ignacio Gutiérrez-Vega
AU - María Elena Quilaqueo
AU - María Elena Quintanilla
AU - David Vásquez
AU - Mario Herrera-Marschitz
AU - Paola Morales Retamales
AU - Mario Rivera-Meza
PY - 2026
DA - 2026/10/13
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1880813
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1880813/full
AB - 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. Methods: 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. Results: 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. Conclusion: 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.
SN - 1663-9812
ER -