Long-term alcohol consumption leads to profound changes in gene expression of the endocannabinoid system in central brain regions crucial for reward, impulse control, and decision-making. This is shown by a post-mortem study on human brain tissue, led by researchers from the Institute of Neuroscience (a joint institution of the Universidad Miguel Hernández de Elche and the CSIC). The findings were published in the journal Addiction.
Alcohol dependence is one of the leading causes of illness and death worldwide, yet treatment options remain limited. "To develop more effective therapies, we need to understand the changes that decades of alcohol consumption cause in the brain," explains Prof. Jorge Manzanares, senior author of the study.
The researchers examined brain tissue from individuals with chronic alcohol dependence (average 35 years of consumption) and compared it with control samples. The focus was on the endocannabinoid system, which regulates reward, motivation, mood, memory, and stress. It includes receptors (CB1, CB2), endogenous ligands, and degrading enzymes such as FAAH and MGLL.
The analysis focused on two key regions of the mesocorticolimbic system: the prefrontal cortex (responsible for judgment, planning, and decision-making) and the nucleus accumbens (a central hub for reward processing and habit formation).
Compared to control samples, the brains of individuals with alcohol dependence showed significant imbalances:
- The expression of the CB1 receptor gene increased by 125% in the prefrontal cortex and by 78% in the nucleus accumbens. CB1 is strongly associated with the reinforcement of addiction-related behaviors and the risk of relapse.
- The expression of the CB2 receptor gene decreased by approximately 50% in both regions. CB2 has neuroprotective and anti-inflammatory functions – its reduction indicates a weakened defense against alcohol-related damage.
- GPR55, a receptor long considered "orphan," showed region-specific changes: +19% in the prefrontal cortex, -51% in the nucleus accumbens. This is the first documentation of such changes in human alcohol dependence.
- The expression of the FAAH gene (enzyme for degrading anandamide) was reduced in the prefrontal cortex but increased by 24% in the nucleus accumbens – altering the availability of endocannabinoids and signal transmission.
The samples came exclusively from the New South Wales Tissue Resource Centre (Australia) and included only individuals with pure alcohol dependence without the use of other illegal drugs. This allowed the effects of alcohol to be isolated.
According to the authors, the changes explain the increased risk of relapse and impaired executive control in alcohol-dependent individuals. The identification of the affected components of the endocannabinoid system in specific brain regions opens up possibilities for more targeted, personalized therapeutic approaches.
The study was funded by, among others, the Instituto de Salud Carlos III, the Spanish Ministry of Science and Innovation, and the Ministry of Health.
