The impact of chronic alcohol consumption on the brain is more significant than many realize, as it leads to profound alterations in gene expression within critical brain regions associated with reward, impulse control, and decision-making. This revelation comes from a study spearheaded by researchers at the Institute for Neurosciences, a collaborative center linked to Miguel Hernández University of Elche (UMH) and the Spanish National Research Council (CSIC). Their findings, published in the journal Addiction, shed light on the biological underpinnings of alcohol addiction and highlight possible therapeutic avenues.
"Alcohol use disorder ranks among the top causes of disease and mortality across the globe. Despite its severe social and health repercussions, treatment options remain frustratingly limited," notes Jorge Manzanares, a professor at UMH and the lead author of this important research. "Gaining insights into the brain's transformations after years of alcohol use is crucial for crafting more effective treatment strategies," he elaborates.
To explore this issue, the scientists examined post-mortem brain samples from individuals who had engaged in chronic alcohol consumption for an average of 35 years. The study specifically targeted the endocannabinoid system, a vital neurobiological network intricately involved in processes related to reward, motivation, and addiction.
This endocannabinoid system plays a pivotal role in regulating essential brain functions, including pleasure, mood, memory, and the response to stress. It comprises various receptors—most notably CB1 and CB2—along with their endogenous ligands and enzymes responsible for breaking down these ligands, such as FAAH and MGLL. "By finely tuning brain activity, this system significantly influences reward and motivational mechanisms," explains Manzanares.
While previous research has indicated that alcohol interacts with the endocannabinoid system, there was a notable lack of evidence derived from human brain tissue. This new study provides a comprehensive examination of how long-term alcohol use modifies the expression of key endocannabinoid-related genes in brain areas crucial for addiction.
Researchers focused on two fundamental components of the mesocorticolimbic system: the prefrontal cortex, which is integral to judgment, planning, and decision-making, and the nucleus accumbens, a central hub for processing rewards and forming habits.
When comparing brain tissue from individuals with alcohol use disorder to control samples from those without addiction, the researchers observed significant imbalances in gene expression. Specifically, they found that the gene for the CB1 receptor experienced a staggering increase—up by 125% in the prefrontal cortex and 78% in the nucleus accumbens. "CB1 is closely associated with the reinforcement of addictive behaviors and the risk of relapse," highlights María Salud García-Gutiérrez, the first author of the study.
On the other hand, the gene responsible for the CB2 receptor showed a reduction of about 50% in both brain regions. "As CB2 serves neuroprotective and anti-inflammatory functions, its decrease implies a potential weakening of the brain's ability to fend off damage caused by alcohol," García-Gutiérrez points out.
Moreover, the research uncovered significant changes in GPR55, a receptor that has long been deemed 'orphan' due to prior uncertainties regarding its natural ligand. The expression of GPR55 increased by 19% in the prefrontal cortex but saw a dramatic decline of 51% in the nucleus accumbens. This marks the first instance of documented changes in GPR55 gene expression in humans suffering from alcohol use disorder.
Additionally, the study revealed region-specific alterations in FAAH, the enzyme tasked with degrading anandamide, a key endocannabinoid that influences anxiety and reward pathways. While FAAH gene expression decreased in the prefrontal cortex, it increased by 24% in the nucleus accumbens; this fluctuation could potentially modify the availability and signaling of endocannabinoids.
A notable strength of this research lies in the utilization of brain tissue samples sourced from the New South Wales Tissue Resource Centre in Australia. All samples were taken from individuals diagnosed with chronic alcohol use disorder who did not engage in the use of other illicit substances. This specificity enables the researchers to isolate the direct effects of alcohol on human brain function. "This methodological approach provides a clearer understanding of how alcohol uniquely affects gene expression in regions of the brain that are vital for addiction," explains García-Gutiérrez.
The authors assert that these discoveries illuminate why individuals grappling with alcohol use disorder often exhibit heightened vulnerability to relapse alongside compromised executive control. By identifying which elements of the endocannabinoid system are impacted and pinpointing the locations of these changes within the brain, the research paves the way for more targeted and personalized therapeutic interventions.
Alongside Jorge Manzanares and María Salud García-Gutiérrez, the study included contributions from Abraham Bailén Torregrosa, Francisco Navarrete, and Auxiliadora Aracil, all members of the Translational Neuropsychopharmacology group at the Institute for Neurosciences and associated 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, a researcher at the Hospital 12 de Octubre Health Research Institute (i+12), also played a role in this investigation.
Funding for this research was provided by the Carlos III Health Institute, the Spanish Ministry of Science and Innovation, and the Spanish Ministry of Health, through national research networks focusing on addiction and health, with additional support from ISABIAL. The Institute for Neurosciences has been recognized as a Severo Ochoa Centre of Excellence.
