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.

JFDB was supported by the Aspirant PhD fellowship from the FRS-FNRS and Van Buuren Funds, BD and AG are supported by the Aspirant PhD fellowship from the FRSFNRS, JC was supported by a fellowship from the Fonds Erasme and SM was supported by a PhD fellowship from FRIA (Belgium) and a Biowin Program from the Walloon Region. AKE is a Research Director of the FRS-FNRS and an investigator of WELBIO. This study was supported by FMRE-Belgium, FRSFNRS (Belgium), Interuniversity Attraction Pole (IUAP-P7/10) from Belgian Federal Scientific Affairs and Action de Recherche Concertée (FWB). The Foundation for Medical Research (FRM, Equipe FRM 2013 to PF), the Centre National de la Recherche Scientifique CNRS UMR 8246, the University Pierre et Marie Curie UM 119, Institut national de la santé et de la recherche médicale INSERM U1130. The Spanish Ministry of Economy (SAF2016-75966R-FEDER), the Generalitat de Catalunya (2014SGR34) and UE Medbioinformatic Project (grant number 634143) to OV. MN was supported by the LabEx Paris-Sciences et Lettres (PSL). The Italian Ministry of Health (RF2009-1549619) to MZ. The Fonds de la Recherche Scientifique-FNRS of the Fédération Wallonie-Bruxelles to ODB.