Chronic alcohol consumption profoundly alters gene expression in key brain regions involved in reward, impulse control, and decision-making, according to a study led by researchers at the Institute for Neurosciences, a joint center of Miguel Hernández University of Elche (UMH) and the Spanish National Research Council (CSIC). Published in the journal Addiction, the work provides new insight into the biological basis of alcohol addiction and points toward potential therapeutic targets.
"Alcohol use disorder is one of the leading causes of disease and death worldwide, yet despite its enormous social and health impact, available treatment options remain limited," explains UMH professor Jorge Manzanares, senior author of the study. "Understanding what changes in the brain after decades of alcohol consumption is essential for developing more effective therapies," he adds.
To address this question, the researchers analyzed post-mortem brain tissue from individuals who had consumed alcohol chronically for an average of 35 years. The study focused on the endocannabinoid system, a key neurobiological network involved in reward, motivation, and addictive behaviors.
The endocannabinoid system regulates fundamental brain functions such as pleasure, mood, memory, and stress response. It consists of receptors—including CB1 and CB2—their endogenous ligands, and enzymes responsible for ligand degradation, such as FAAH and MGLL. "This system acts as a fine-tuned modulator of brain activity and plays a central role in reward and motivation," Manzanares explains.
Previous studies had shown that alcohol interacts with the endocannabinoid system, but evidence from human brain tissue was scarce. This study provides a detailed picture of how chronic alcohol use alters the expression of key endocannabinoid genes in brain regions critical to addiction.
Researchers examined two core components of the mesocorticolimbic system: the prefrontal cortex, involved in judgment, planning, and decision-making, and the nucleus accumbens, a central hub for reward processing and habit formation.
Compared with control samples from individuals without addiction, brain tissue from people with alcohol use disorder showed marked gene expression imbalances. Expression of the CB1 receptor gene increased by 125% in the prefrontal cortex and by 78% in the nucleus accumbens. "CB1 is closely linked to reinforcement of addictive behaviors and relapse risk," explains UMH professor María Salud García-Gutiérrez, first author of the study.
In contrast, expression of the CB2 receptor gene decreased by approximately 50% in both regions. "Because CB2 has neuroprotective and anti-inflammatory functions, its reduction suggests a weakening of the brain's defenses against alcohol-induced damage," García-Gutiérrez notes.
The study also revealed striking alterations in GPR55, a receptor long considered 'orphan' due to uncertainty about its natural ligand. GPR55 expression increased by 19% in the prefrontal cortex but dropped by 51% in the nucleus accumbens. This is the first study to document changes in GPR55 gene expression in humans with alcohol use disorder.
In addition, the researchers detected region-specific changes in FAAH, the enzyme responsible for degrading anandamide, an endocannabinoid involved in anxiety and reward. FAAH gene expression was reduced in the prefrontal cortex but increased by 24% in the nucleus accumbens, potentially altering endocannabinoid availability and signaling.
A major strength of the study is the use of brain tissue samples from the New South Wales Tissue Resource Centre in Australia. All samples came from individuals with chronic alcohol use disorder who did not consume other illicit drugs, allowing the researchers to isolate the specific effects of alcohol on the human brain. "This approach provides a much clearer picture of how alcohol alone reshapes gene expression in brain regions central to addiction," García-Gutiérrez explains.
According to the authors, these findings help explain why individuals with alcohol use disorder show increased relapse vulnerability and impaired executive control. Identifying which components of the endocannabinoid system are altered, and where in the brain these changes occur, opens the door to more targeted and personalized therapeutic strategies.
In addition to Jorge Manzanares and María Salud García-Gutiérrez, the study was authored by Abraham Bailén Torregrosa, Francisco Navarrete, and Auxiliadora Aracil, members of the Translational Neuropsychopharmacology of Neurological and Psychiatric Disorders group at the Institute for Neurosciences and affiliated with the Primary Care Addiction Research Network of the Carlos III Health Institute and the Alicante Institute for Health and Biomedical Research (ISABIAL). Gabriel Rubio, researcher at the Hospital 12 de Octubre Health Research Institute (i+12), also contributed to the study.
The research was funded by the Carlos III Health Institute, the Spanish Ministry of Science and Innovation, and the Spanish Ministry of Health, through national research networks in addiction and health, with additional support from ISABIAL. The Institute for Neurosciences is accredited as a Severo Ochoa Centre of Excellence.
