Genetic alterations discovered in brains with alcoholism

Researchers from the Institute of Neurosciences (IN), a joint center of the Miguel Hernández University of Elche (UMH) and the Higher Council for Scientific Research, have led a study in which they have identified genetic alterations “key” in the brain of people with alcoholism.

The work, published in the magazine addictionemphasizes that chronic alcohol consumption “profoundly alters” the expression of endocannabinoid system genes in prominent regions of the brain and shows how these changes affect areas involved in reward, impulse control and decision making. Thus, it opens “new avenues” to understand the biology of addiction and improve its treatment, as indicated by the IN in a statement.

“Alcoholism is one of the main causes of illness and death in the world, but, despite its social and health impact, the available therapeutic options remain limited,” explains Jorge Manzanaresleader of the study and director of the translational neuropsychopharmacology of neurological and psychiatric diseases laboratory, who pointed out that, “therefore, understanding what changes in the brain after decades of consumption is key to developing more effective therapies.”

In this context, the study focused on analyzing the neurobiological mechanisms associated with the disorder alcohol use by examining postmortem brain tissue from people who had chronically consumed alcohol for an average of 35 years.

Specifically, the researchers looked for changes in the endocannabinoid system, closely linked to reward and addiction mechanisms. The endocannabinoid system is a chemical communication network that regulates functions as basic as pleasure, memory, mood and stress response. It is made up of receptors, such as CB1 and CB2its natural ligands and the enzymes responsible for its degradation, including FAAH and MGLL. “This system acts as a fine modulator of brain functioning and plays a central role in reward and motivation processes,” says Manzanares.

According to the researchers, until now it was known that alcohol interacts with this system, but there was little data based on studies on the human brain. For this reason, the IN considers that the new work “provides a detailed view of how chronic consumption alters the expression of key genes of the endocannabinoid system in regions involved in addiction.”

Study of two “fundamental” areas

The scholars analyzed two “fundamental” areas of the mesocorticolimbic system: the prefrontal cortex, related to judgment, planning and decision making, and the nucleus accumbens, considered the nerve center of reward and habit formation.

When comparing samples of people with alcohol use disorder with those of individuals without addictionthe team observed a “notable imbalance” in the expression of several genes in the endocannabinoid system.

First, they detected a marked increase in the receptor CB1: the levels of the gene that codes for it increased by a 125% in the prefrontal cortex and 78% in the nucleus accumbens. “This receptor is closely involved in reinforcing addictive behaviors and in the risk of relapse,” comments the researcher. María Salud Gutiérrez Garcíafirst author of the study.

In contrast, the expression of the receptor gene CB2 was reduced by approximately 50% in both regions. “Given that the CB2 receptor fulfills neuroprotective and anti-inflammatory functions, its decrease suggests a deterioration of the brain’s defense mechanisms against alcohol-induced damage,” details the researcher.

A “striking finding” for the researchers was the alteration of the receptor GPR55known as “orphan” because for years it was not known with certainty what its natural ligand was. The researchers found higher levels in the prefrontal cortex, with an increase in 19%but “significantly lower” in the nucleus accumbens, with a reduction in 51%.

This study of IN is “the first to document changes in this gene in humans with alcohol use disorder.” In addition, they observed changes in the enzyme FAAHresponsible for degrading anandamide, a cannabinoid generated by the nervous system that influences anxiety and pleasure.

In people with alcoholism, the gene expression of FAAH was smaller in the prefrontal cortex, but a 24% greater in the nucleus accumbens, which could alter the availability of these regulatory substances.

Samples

The IN has highlighted that one of the “strengths” of the work is the use of brain tissue samples from the New South Wales Tissue Resource Centre, in Sydney (Australia). These samples belonged to people with chronic alcoholism who did not consume other illicit drugswhich made it possible to isolate the specific effects of alcohol on the human brain without the usual interference of polydrug use. “This approach provides a clearer picture of how alcohol alone remodels gene expression in brain regions key to addiction,” he says. Garcia Gutierrez.

According to the authors, these findings “help to better understand why the brains of people with alcohol use disorder present greater vulnerability to relapse and a lower capacity for executive control.

“Identifying which components of the endocannabinoid system are altered and in which brain regions opens the door to new therapeutic targets more specific and personalized”, they have highlighted from the IN.

Authors

The authors of the study are part of the Primary Addiction Care Research Network of the Carlos III Health Institute (ISCIII), as well as the Health and Biomedical Research Institute of Alicante (Isabial).

The work has also had the participation of the researcher Gabriel Rubiofrom the Health Research Institute of Hospital 12 de Octubre (i+12), and has been possible thanks to funding from the ISCIII, the Ministry of Science, Innovation and Universities and the Ministry of Health, within the framework of national research networks in addictions and health, with the support of Isabial. The IN is accredited as a Severo Ochoa Center of Excellence.