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V.Deroche, C.Herry et al. dans Neuropsychopharm

From discrepancy to paradox through optogenetic: Inactivation of the Prelimbic cortex can indeed inhibit and promote cocaine seeking.

Le 8 avril 2014

Frequency of Cocaine Self-Administration Influences Drug Seeking in the Rat: Optogenetic Evidence for a Role of the Prelimbic Cortex. Martín-García E, Courtin J, Renault P, Fiancette JF, Wurtz H, Simonnet A, Levet F, Herry C, Deroche-Gamonet V. Neuropsychopharmacology. 2014 Mar 17. doi: 10.1038/npp.2014.66.

Cover illustration:

Elena Martin-Garcia et al. have evidenced that frequency of cocaine use influences cocaine incentive effects. In both humans and animals, cocaine addiction is associated with high frequency use (binge-like pattern) and high drug-induced seeking. The relationships between high frequency use and high drug-induced seeking remained hypothetical. They manipulated frequency of cocaine self-administration in rats and investigated whether it influenced cocaine seeking. As compared to cocaine low frequency users, high frequency users showed increased cocaine-induced cocaine seeking as measured in cocaine-induced reinstatement. 

Elena Martin-Garcia et al. revealed that high frequency cocaine intake promotes a recruitment of the prelimbic cortex to control cocaine seeking. c-Fos expression measured in prelimbic and infralimbic cortex, basolateral amygdala and nucleus accumbens shell and core revealed a distinct functional recruitment of the circuit in high and low frequency users, with the prelimbic cortex playing a major role in high frequency users. Accordingly optogenetic inactivation of the prelimbic cortex in high frequency users reduced cocaine-induced seeking, while activation in the low frequency users was ineffective.

Elena Martin-Garcia et al. have solved an apparent discrepancy. Depending on experiments, inactivation of the prelimbic cortex had been shown to produce decrease or increase in drug seeking. Here in the same (high frequency users) rats, optogenetic inactivation of the prelimbic cortex decreased cocaine-induced reinstatement and increased cocaine seeking in self-administration. What looked like so far as a discrepancy between independent studies revealed as a prelimbic paradox. Underlying psychobiological mechanisms will be investigated.

High frequency intake and high drug-induced seeking are associated with cocaine addiction in both human and animals. However, their relationships and neurobiological underpinnings remain hypothetical. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and nucleus accumbens (NAc) have been shown to play a role in cocaine seeking. However, their involvement in regulating high frequency intake and high cocaine-induced seeking is unclear. We manipulated frequency of cocaine self-administration and investigated whether it influenced cocaine seeking. The contribution of the aforementioned structures was evaluated using changes in expression of the immediate early gene c-Fos and targeted optogenetic manipulations. Rats that self-administered at High frequency (short inter-infusion intervals allowed by short time-out) showed higher cocaine-induced seeking than Low frequency rats (long inter-infusions intervals imposed by long time-out), as measured with cocaine-induced reinstatement. c-Fos was enhanced in High frequency rats in the prelimbic (PL) and infralimbic (IL) areas of the mPFC, the BLA, and the NAc core and shell. Correlational analysis of c-Fos revealed that the PL was a critical node strongly correlated with both the IL and NAc core in High frequency rats. Targeted optogenetic inactivation of the PL decreased cocaine-induced reinstatement, but increased cocaine self-administration, in High frequency rats. In contrast, optogenetic activation of the PL had no effect in Low frequency rats. Thus, High frequency intake promotes a PL-dependent control of cocaine seeking, with the PL exerting a facilitatory or inhibitory effect, depending on operant contingencies. Individual differences in cocaine-induced PL activation might be a source of vulnerability for poorly controlled cocaine-induced seeking and/or cocaine intake. 


Véronique Deroche-Gamonet / Neurocentre Magendie (veronique.deroche @
Dernière mise à jour le 09.04.2014

1er auteur

Elena Martín García
Postdoctoral researcher in neuroscience in University Pompeu Fabra and assistant professor in psychobiology in University Autonomous of Barcelona.