title: Frequency of cocaine self-administration influences drug seeking in the rat: optogenetic evidence for a role of the prelimbic cortex.
abstract: 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 have 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 on 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.
authors.affiliation: 1] INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France [2] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France [3] Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, C/ Dr Aiguader 88, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: 1] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France [2] INSERM U862, Neuronal Circuits of Associative Learning, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Courtin
authors.affiliation: 1] INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France [2] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Prisca
authors.initials: P
authors.lastname: Renault
authors.affiliation: 1] INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France [2] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fiancette
authors.affiliation: 1] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France [2] INSERM U862, Neuronal Circuits of Associative Learning, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Wurtz
authors.affiliation: 1] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France [2] INSERM U862, Neuronal Circuits of Associative Learning, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Simonnet
authors.affiliation: 1] University of Bordeaux, Bordeaux Imaging Center, Bordeaux, France [2] CNRS, Bordeaux Imaging Center, Bordeaux, France [3] INSERM, Bordeaux Imaging Center, Bordeaux, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Levet
authors.affiliation: 1] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France [2] INSERM U862, Neuronal Circuits of Associative Learning, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Herry
authors.affiliation: 1] INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, 146 rue Léo Saignat, Bordeaux, Cedex, France [2] University of Bordeaux, 146 Rue Léo Saignat, Bordeaux, Cedex, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Deroche-Gamonet
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D062308:Optogenetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013997:Time Factors
chemical_list: D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine