Deroche-Gamonet V1,2, Kasanetz F3, Lafourcade M4, Fiancette JF1,2, Renault P1,2, Revest JM1,2, Piazza PV1,2, Manzoni O5
1NeuroCentre Magendie, Bordeaux, France
2Université de Bordeaux, Bordeaux, France
3Universität Bern, Bern, Switzerland
4MIT, Cambridge, USA
5Inmed, Marseille, France
Drug addiction is a chronic relapsing disorder characterized by a loss of control over drug use and drug seeking that occurs in a limited number of users, after more or less protracted use. Drug 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 intravenous 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 receptor-dependent 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-like 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 the primary sites of action of cocaine. This default of counteradaptations in the 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.