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Transition to cocaine addiction: sequential hierarchical loss of synaptic
plasticity from the nucleus accumbens to the prelimbic cortex?
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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.
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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
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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.