Martín-García Elena, Courtin Julien, Renault Prisca, Fiancette Jean-François, Wurtz Hélène, Simonnet Amélie, Levet Florian, Herry Cyril, Deroche-Gamonet Véronique
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.
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.
Neuropsychopharmacology. 2014 Sep;39(10):2317-30. doi: 10.1038/npp.2014.66. Epub 2014 Mar 17.
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.
高频摄入和高药物诱导觅药行为在人类和动物中均与可卡因成瘾相关。然而，它们之间的关系及其神经生物学基础仍属假设。内侧前额叶皮质（mPFC）、基底外侧杏仁核（BLA）和伏隔核（NAc）已被证明在可卡因觅药行为中发挥作用。然而，它们在调节高频摄入和高可卡因诱导觅药行为中的作用尚不清楚。我们操纵了可卡因自我给药的频率，并研究其是否影响可卡因觅药行为。使用即刻早期基因c-Fos表达的变化和靶向光遗传学操作评估了上述结构的作用。高频自我给药的大鼠（短超时允许短输注间隔）比低频大鼠（长超时导致长输注间隔）表现出更高的可卡因诱导觅药行为，这通过可卡因诱导的复吸来衡量。高频大鼠的mPFC的前边缘（PL）和下边缘（IL）区域、BLA以及NAc核心和壳层中的c-Fos增强。对c-Fos的相关性分析表明，在高频大鼠中，PL是与IL和NAc核心均强烈相关的关键节点。对高频大鼠进行PL的靶向光遗传学失活可减少可卡因诱导的复吸，但增加可卡因自我给药。相反，PL的光遗传学激活对低频大鼠没有影响。因此，高频摄入促进了对可卡因觅药行为的PL依赖性控制，PL根据操作条件发挥促进或抑制作用。可卡因诱导的PL激活的个体差异可能是可卡因诱导的觅药行为和/或可卡因摄入控制不佳的易感性来源。
