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Oral ! Transition to cocaine addiction: sequential hierarchical loss of synaptic plasticity from the nucleus accumbens to the prelimbic cortex? ! Deroche-Gamonet V1,2, Kasanetz F1,2, Berson N1,2, Lafourcade M1,2,3, Balado E1,2, Fiancette, JF1,2, Renault P1,2, Revest J-M1,2, Manzoni O1,2,3, Piazza PV1,2. ! 1Inserm CRI U862, 146 rue Léo Saignat, 33076 Bordeaux, France of Bordeaux, 146 rue Léo Saignat, 33077 Bordeaux, France 3Inserm U901, INMED, Université de la Méditerranée UMR S901 Aix-Marseille 2, Marseille, 13009, France 2University ! Cocaine addiction is a chronic relapsing disorder characterized by a loss of control over drug use and drug seeking that occurs in about 20% of users, after more or less protracted use. Cocaine use induces countless modifications in brain physiology. Which ones actually contribute to addiction is difficult to address without preparations specifically modeling uncontrolled drug use. We developed a model which uniquely allows observing transition to cocaine addiction in about 20% of rats, after protracted cocaine self-administration. This model allowed us identifying correlates of transition to cocaine addiction. In the nucleus accumbens, a form of synaptic plasticity, i.e. the NMDA receptordependent long-term depression (NMDAR-LTD), is suppressed in all subjects, after early drug use. Rats shifting to addiction maintain a permanent impairment of NMDAR-LTD, while rats keeping control on drug use recover it. In parallel, in the prelimbic cortex, mGluR2/3-dependent LTD is specifically abolished in rats showing addiction-like behavior; this form of plasticity being unaltered both after early drug use and in non-addicted rats. These data challenge the common conceptualization in which transition to addiction is seen as resulting from the development of brain alterations specifically in vulnerable subjects. Instead, transition to addiction is associated with the inability of vulnerable rats to engage active processes to counteract early cocaine-induced effects occurring in all users in drug primary sites of action. This default of counteradaptations in drug primary sites of action could underlie secondary specific adaptations in higher executive brain areas such as the one observed in the prelimbic cortex. Altogether, these results underline the importance of the behavioral preclinical models used in addiction research and more generally in experimental psychopathology.