Summary: A new study reports mice lacking the Maged1 gene are unable to acquire an addiction to cocaine.
Source: Université Libre de Bruxelles, Belgium.
Cocaine can have a devastating effect on people. It directly stimulates the brain’s reward center, and, more importantly, induces long-term changes to the reward circuitry that are responsible for addictive behaviors. Alban de Kerchove d’Exaerde from the Université Libre de Bruxelles, Belgium, and his colleagues have now uncovered that a gene called Maged1 plays a crucial role in controlling these pathological changes. This finding, published today in EMBO Reports, opens the door to further investigations into the molecular mechanisms underlying addiction-associated adaptations in the brain.
Maged1 is a member of a family of genes that first gained attention because they are active in tumors. However, Maged1 also functions in the brain and has been shown to play a role in neural fating and response to antidepressants. Moreover, activation of the Maged1 gene is altered by chronic cocaine treatment. Hence, de Kerchove d’Exaerde and colleagues set out to investigate whether Maged1 plays a role in cocaine addiction.
Every animal, including humans, feels pleasure when engaging in certain behaviors, such as eating, drinking or procreating. Rewarding stimuli lead to the release of dopamine from the ventral tegmental area (VTA) of the brain to other brain regions that are connected to the VTA, mainly in the Nucleus Accumbens (NAc), the hub of the reward system. Cocaine directly affects the reward system by blocking the removal of dopamine from the synapses, leading to a dopamine surge that over-activates the circuitry. This excess of dopamine induces long-lasting changes in the brain, eventually leading to addiction.
Some of the cocaine-induced changes occur in the prefrontal cortex. In healthy animals, the prefrontal cortex controls behaviors such as inhibitory control and emotion regulation. Alterations in these structures after cocaine abuse are thought to mediate many of the symptoms that characterize addiction such as drug-seeking, loss of control and poor decision making.
De Kerchove d’Exaerde and colleagues observed that mice lacking the Maged1 gene were entirely unresponsive to cocaine and that the release of dopamine in the NAc is diminished. They did not show any reaction normally observed after cocaine treatment, such as drug sensitization, an increased effect of the drug following repeated doses or addictive behavior like seeking up places where the animal expects a cocaine reward or auto-administration of the drug. In a subsequent set of experiments, the researchers scrutinized the role of Maged1 in different brain areas and found that it is specifically required in the prefrontal cortex and not in the neurons producing dopamine in the VTA for the development of cocaine sensitization and dopamine release.
Only very few mutations are known to induce a complete lack of behavioral response to cocaine. Other members of this small group are established components of the reward system. Maged1 thus serves as a promising new entry point into the analysis of the mechanisms underlying drug addiction.
Funding: FNRS, FRIA, Action de Recherche Concertée (FWB), Fonds Erasme, Fondation ULB funded this study.
Source: Alban de Kerchove d’Exaerde – Université Libre de Bruxelles, Belgium
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine” by Jean‐François De Backer, Stéphanie Monlezun, Bérangère Detraux, Adeline Gazan, Laura Vanopdenbosch, Julian Cheron, Giuseppe Cannazza, Sébastien Valverde, Lídia Cantacorps, Mérie Nassar, Laurent Venance, Olga Valverde, Philippe Faure, Michele Zoli, Olivier De Backer, David Gall, Serge N Schiffmann, and Alban de Kerchove d’Exaerde in EMBO Reports. Published July 12 2018.
Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocainen
Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self‐administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico‐accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine‐mediated behavioural sensitization, and its expression in the PFC is also required for cocaine‐induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction.