Cocaine addiction: Role of Maged1 beyond the cerebral reward circuit
Drug addiction is considered to be a psychiatric illness that manifests itself in increased tolerance, compulsive use and loss of control, and causes almost 12 million deaths every year - more than all cancers put together.
The origins of this psychiatric illness lie in genetic and environmental factors. The genetic component of a person's vulnerability to addiction ranges between 40% and 60% and concerns genes linked to neurotransmitter systems such as dopamine, serotonin, opioid, nicotinic and cannabinoid receptors. Addiction to drugs results in an artificial increase in dopamine, the neurotransmitter linked to the brain's reward system.
In a previous study, Alban de Kerchove d'Exaerde's team (WEL Research Institute - ULB) discovered, using mouse models, the central role of an unsuspected gene in cocaine addiction: Maged1.
In this new publication, the team showed that the region of the brain where the Maged1 gene plays an essential role in addiction lies outside the reward circuit generally associated with drug addiction, which was completely unexpected. The mechanisms underlying the major effects of Maged1 in cocaine addiction involve specific epigenetic modifications with a major influence on the expression of many other genes. In mouse models, inhibition of one of the new genes identified as a partner of Maged1 for these epigenetic modifications, USP7, abolished addictive behaviours.
To study the relevance of the mechanisms identified in mice for humans, a genetic analysis was carried out on blood samples taken from cocaine-dependent patients in collaboration with a team of psychiatrists from the Université de Paris Cité. A polymorphism of Maged1 and USP7 was identified, suggesting a correlation with vulnerability to addiction-related behaviours in response to cocaine.
Reference : Cheron et al., Histone H2A monoubiquitination in the thalamus regulates cocaine, Nat Commun (2023) 14 : 8481
Source : Press release ULB
Illustration : Colin Davis on unsplash