Suchergebnisse

Several lines of evidence support that food overconsumption may be related to the role of the endogenous opioid system in the control of food palatability. The opioid system, and particularly the delta opioid receptor (DOR), plays a crucial role in the regulation of food rewarding properties. In our study, we used operant conditioning maintained by chocolate-flavoured pellets to investigate the role of DOR in the motivation for palatable food and the structural plasticity changes promoted by this behaviour. For this purpose, we evaluated the specific role of this receptor in the behavioural and neuroplastic changes induced by palatable food in the prefrontal cortex (PFC), hippocampus (HCP) and nucleus accumbens (NAc) in constitutive knockout (KO) mice deficient in DOR. Mutant mice and their wild-type littermates were trained to obtain chocolate-flavoured pellets on fixed ratio 1 (FR1), FR5 and progressive ratio (PR) schedule of reinforcement. No significant differences between genotypes were revealed on operant behaviour acquisition in FR1. DOR knockout mice displayed lower number of active lever-presses than wild-type mice on FR5, and a similar decrease was revealed in DOR KO mice in the breaking point during the PR. This operant training to obtain palatable food increased dendritic spine density in the PFC, HCP and NAc shell of wild-type, but these plasticity changes were abolished in DOR KO mice. Our results support the hypothesis that DOR regulates the reinforcing effects and motivation for palatable food through neuroplastic changes in specific brain reward areas. ; This work was supported by the DG Research of the European Commission FP7 (#HEALTH-F2 2013-602891), the Spanish 'RETICS-Instituto de Salud Carlos III' (#RD12/0028/0023), the Spanish 'Ministerio de Ciencia e Innovación' (#SAF2011-29864), the Spanish 'Ministerio de Economia y Competitividad' (#SAF-2014-59648P), the 'Plan nacional sobre drogas' (#PNSD-2013-5068) and the Catalan Government 'AGAUR-Generalitat de Catalunya' (#2009SGR00731 and #2014-SGR-1547). The FEDER funds support is also acknowledged. S.M. was supported by FI predoctoral fellowship of the Catalan Government; S.M-N. was supported by CAPES fellowship of the Brazilian Government (Programa Ciência Sem Froteiras). We thank Elysia James for invaluable technical assistance in the structural plasticity study

An increasing perspective conceptualizes obesity and overeating as disorders related to addictive-like processes that could share common neurobiological mechanisms. In the present study, we aimed at validating an animal model of eating addictive-like behavior in mice, based on the DSM-5 substance use disorder criteria, using operant conditioning maintained by highly palatable chocolate-flavored pellets. For this purpose, we evaluated persistence of food-seeking during a period of non-availability of food, motivation for food, and perseverance of responding when the reward was associated with a punishment. This model has allowed identifying extreme subpopulations of mice related to addictive-like behavior. We investigated in these subpopulations the epigenetic and proteomic changes. A significant decrease in DNA methylation of CNR1 gene promoter was revealed in the prefrontal cortex of addict-like mice, which was associated with an upregulation of CB1 protein expression in the same brain area. The pharmacological blockade (rimonabant 3 mg/kg; i.p.) of CB1 receptor during the late training period reduced the percentage of mice that accomplished addiction criteria, which is in agreement with the reduced performance of CB1 knockout mice in this operant training. Proteomic studies have identified proteins differentially expressed in mice vulnerable or not to addictive-like behavior in the hippocampus, striatum, and prefrontal cortex. These changes included proteins involved in impulsivity-like behavior, synaptic plasticity, and cannabinoid signaling modulation, such as alpha-synuclein, phosphatase 1-alpha, doublecortin-like kinase 2, and diacylglycerol kinase zeta, and were validated by immunoblotting. This model provides an excellent tool to investigate the neurobiological substrate underlying the vulnerability to develop eating addictive-like behavior. ; This work was supported by the DG Research of the European Commission FP7 (No. HEALTH-F2 2013-602891), the Spanish 'RETICS-Instituto de Salud Carlos III' (No. RD12/0028/0023), the Spanish 'Ministerio de Ciencia e Innovación' (No. SAF2011-29864), and the Catalan Government 'AGAUR-Generalitat de Catalunya' (Nos. 2009SGR00731 and 2014-SGR-1547). The FEDER funds support is also acknowledged. SM and AB were supported by FI predoctoral fellowships of the Catalan Government, and JG-C was supported by a 'Juan de la Cierva' postdoctoral fellowship from the Spanish 'Ministerio de Ciencia e Innovación'. Also support by the Italian Ministry of University and Research under grants FIRB-RBFR12DELS to CDA and PRIN2010-11 to MM is gratefully acknowledged. The authors declare no conflict of interest.