Alcoholism causes a cerebral inflammatory reaction, and a decrease in the amount of a natural anti-inflammatory agent in a key area associated with emotions. Restoring levels of the latter makes mice less addicted to alcohol!
According to a French Public Health survey conducted in January 2020, 10% of French people aged between 18 and 75 years old drink alcohol on a daily basis, which represents a consumption at risk of dependency, and 41,000 deaths are attributable to alcohol per year, 30,000 of them among men and 11,000 among women.
However, the mechanisms of alcohol addiction are not yet very clear and there is no effective treatment… One lead is based on inflammation and brain immunity, and it is this that Reesha Patel, from the La Jolla Institute in California, and her colleagues have explored, revealing a potential treatment based on anti-inflammatory drugs.
Indeed, heavy and repeated consumption of alcohol causes an inflammatory reaction in the brain which participates in the development and maintenance of the addiction, in particular by provoking changes in neuronal activity in the brain regions associated with the addiction, for example the reward circuit. A better understanding of the neuro-immune reaction induced by alcohol would make it possible to develop therapies against alcoholism, which are sorely lacking today.
Immunity is a complex phenomenon: while pro-inflammatory agents trigger and maintain the immune response (to protect tissues from a pathogen or hazard), there are also anti-inflammatory agents that attenuate it, limiting inflammation and thus secondary cellular damage.
It has been suggested in preclinical studies with alcoholic patients that certain anti-inflammatory drugs (e.g. minocycline, generally used as an anti-acne medication) would reduce their alcohol consumption.
One of the most potent anti-inflammatory agents is interleukin-10 (IL-10), which is produced throughout the brain by microglia (star-shaped non-neuronal brain cells) and regulatory T-lymphocytes (agents of the immune system). IL-10 has already been implicated in alcoholism: it is believed to reduce the alcohol consumption of some patients when it is “infused” directly into their tonsils. This small almond-shaped brain structure plays an important role in our emotions, behaviour and motivation and, as part of the reward circuit, is strongly implicated in alcohol abuse: a disturbance of the amygdala, especially of its so-called “GABAergic” neurons, is linked to high anxiety and excessive drinking behaviour.
To understand the precise mechanisms of the role of anti-inflammatory drugs in neurobiology and alcohol-related behaviour, the researchers therefore made mice alcoholic by exposing them to an alcoholic drink five days a week for a month.
In this situation, the rodents exhibited many typical addictive behaviours, including increased anxiety and increased alcohol consumption. Patel and his colleagues then found that the brains of the alcoholic mice were on the whole very inflamed, which resulted in a multiplication of immune cells, microglia and regulatory T-cells, among other things, that produce IL-10.
Surprisingly, however, their tonsils were an exception, including one of the central nuclei, because the concentration of the anti-inflammatory IL-10 was much lower there than in the non-diseased mice. This defect was also correlated with the overactivation of GABAergic neurons in the tonsil.
By restoring the correct IL-10 levels in the tonsils of alcoholic mice (thanks to a viral vector injected into their brains), the researchers regulated the activity of their tonsils and the rodents were less anxious and had much less desire to drink alcohol again.
IL-10 was binding to these specific receptors in the amygdala, reducing the activity of the GABAergic neurons via cell signalling pathways that the researchers identified.
The lack of IL-10 anti-inflammatory drugs in the amygdala is a good contributor to alcohol dependence and the escalation of drink consumption. Reducing the inflammation associated with excessive alcohol consumption would therefore be possible through the use of anti-inflammatory drugs such as minocycline or by directly targeting IL-10 receptors.
These are therapies that researchers hope to test in humans in the near future.