Frequency of Cocaine Self-Administration Influences Drug Seeking in the Rat: Optogenetic Evidence for a Role of the Prelimbic Cortex

Elena Martín-García, Julien Courtin, Prisca Renault, Jean- François Fiancette, Hélène Wurtz, Amélie Simonnet, Florian Levet, Cyril Herry, Véronique Deroche-Gamonet
Neuropsychopharmacol. 2014-03-17; 39(10): 2317-2330
DOI: 10.1038/npp.2014.66

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1. Neuropsychopharmacology. 2014 Sep;39(10):2317-30. doi: 10.1038/npp.2014.66. Epub
2014 Mar 17.

Frequency of cocaine self-administration influences drug seeking in the rat:
optogenetic evidence for a role of the prelimbic cortex.

Martín-García E(1), Courtin J(2), Renault P(3), Fiancette JF(3), Wurtz H(2),
Simonnet A(2), Levet F(4), Herry C(2), Deroche-Gamonet V(3).

Author information:
(1)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.
(2)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.
(3)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.
(4)1] University of Bordeaux, Bordeaux Imaging Center, Bordeaux, France [2] CNRS,
Bordeaux Imaging Center, Bordeaux, France [3] INSERM, Bordeaux Imaging Center,
Bordeaux, France.

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.

DOI: 10.1038/npp.2014.66
PMCID: PMC4138740
PMID: 24633559 [Indexed for MEDLINE]


Auteurs Bordeaux Neurocampus