Suchergebnisse

High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high-caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations. ; This work was supported by the European Commission, FP7 (#HEALTH‐F2‐2013‐602891) to R.M.; the Spanish Ministerio de Economía y Competitividad‐MINECO (#SAF2014‐59648‐P‐FEDER), the Spanish Instituto de Salud Carlos III, RETICS‐RTA (#RD12/0028/0023‐FEDER) and the Generalitat de Catalunya, AGAUR (#2014‐SGR‐1547) to R.M. The financial support of the Fundació La Marató‐TV3 (#201620‐30) is also acknowledged. We would like to thank the Advance Light Microscopy Unit of the Center for Genomic Regulation for their technical assistance on the acquisition and processing of microscopy images. S. M‐N. was supported by CAPES fellowship of the Brazilian Government (Programa Ciência Sem Fronteiras).

The version of record of this article, first published in Psychopharmacology, is available online at Publisher's website: http://dx.doi.org/10.1007/s00213-021-05820-z ; Rationale Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. Objectives Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. Results Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. Conclusions Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use. ; We acknowledge the financial support of the Spanish "Instituto de Salud Carlos III" (#RD16/0017/0020 to R.M, #RD16/0017/003 to M.F., and #CIBEROBN to R. dl T.), Spanish "Ministerio de Sanidad y Política Social-Investigación Clínica Independiente" (#EC10-166 to M.F.), the Catalan Government (#2017 SGR 669 and #TECCIT2014 and 2015-NeuroPhar to R.M., #2017-SRG-316 to M.F., and #2017-SGR-138 and #TECCIT2014 and 2015-BAPP to R dl T.). M.M. was a "Beatriu de Pinós" fellow (#2010-BP-B00221). Partial support of FEDER funds is also acknowledged. The authors declare no conflict of interest (financial and non-financial). ; Peer Reviewed ; Postprint (published version)

Altres ajuts: We acknowledge the financial support of the Spanish "Instituto de Salud Carlos III" (#CIBEROBN to R. dl T.), the Catalan Government (#TECCIT2014 and 2015-NeuroPhar to R.M., and #TECCIT2014 and 2015-BAPP to R dl T.). M.M. was a "Beatriu de Pinós" fellow (#2010-BP-B00221). Partial support of FEDER funds is also acknowledged. ; Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.

Obesity represents an important risk factor contributing to the global burden of disease. The current obesogenic environment with easy access to calorie-dense foods is fueling this obesity epidemic. However, how these foods contribute to the progression of feeding behavior changes that lead to overeating is not well understood and needs systematic assessment. Using novel automated methods for the high-throughput screening of behavior, we here examine mice meal pattern upon long-term exposure to a free-choice chocolate-mixture diet and a high-fat diet with face validity for a rapid development of obesity induced by unhealthy food regularly consumed in our societies. We identified rapid diet-specific behavioral changes after exposure to those high-caloric diets. Mice fed with high-fat chow, showed long-lasting meal pattern disturbances, which initiate with a stable loss of circadian feeding rhythmicity. Mice receiving a chocolate-mixture showed qualitatively similar changes, though less marked, consisting in a transient disruption of the feeding behavior and the circadian feeding rhytmicity. Strikingly, compulsive-like eating behavior is triggered immediately after exposure to both high-fat food and chocolate-mixture diet, well before any changes in body weight could be observed. We propose these changes as behavioral biomarkers of prodromal states of obesity that could allow early intervention. ; The laboratory of M.D. is supported by DIUE de la Generalitat de Catalunya (Grups consolidats SGR 2014/1125). This work was supported by Fondation Jérôme Lejeune (Paris, France), MINECO (SAF2013‐49129‐C2‐1‐R; SAF2016‐79956‐R), CDTI ('Smartfoods') and EU (Era Net Neuron PCIN‐2013‐060) and the Catalan foundation 'La Marató de TV3' (#2016/20‐30). The CRG is a Center of Excellence Severo Ochoa SEV‐2012‐0208. The CIBER of Rare Diseases is an initiative of the ISCIII. The laboratory of C.N. acknowledge the funding from the Spanish Ministry of Economy and Finance (MINECO), grant number BFU2011‐28575. J.E. received the FI grant from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya. The laboratory of R.M. was supported by the DG Research of the European Commission FP7 (#HEALTH‐F2 2013‐602891 and PHECOMP #LHSM‐CT‐2007‐037669), the Spanish 'RETICS‐Instituto de Salud Carlos III' (#RD16/0017/0020), the Spanish 'Ministerio de Economia y Competitividad' (#SAF‐2014‐59648P), the 'Plan nacional sobre drogas' (#PNSD‐2013‐5068), the Catalan Government 'AGAUR‐Generalitat de Catalunya' (#2014‐SGR‐1547) and the Catalan foundation 'La Marató de TV3' (#2016/20‐30).

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.