Role of DOR in neuronal plasticity changes promoted by food-seeking behaviour

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 stud

Antidepressant effects of total tertiary alkaloid fraction of Cissampelos sympodialis Eichler in rodents

The purpose of the present study was to evaluate the effects of total tertiary alkaloid fraction (TTAF) of Cissampelos sympodialis Eichler (Menispermaceae) on two animal models of depression: a) forced swim test and b) reserpine test. Treatment of mice with TTAF (12.5 mg/kg) reduced the total immobility time. It also reversed the reserpine-induced hypothermia, demonstrating an antidepressant effect in both models. Additionally, TTAF treatment did not modify the ambulation and rearing evaluated in open field test in order to investigate if the immobility time reduction found in the forced swimming test was caused by locomotive activity stimulation. Since warifteine is one of the main alkaloids present in the TTAF of C. sympodialis, and it has inhibitory activity of the phosphodiesterase enzyme, it may be responsible by the antidepressant effect found in the fraction studied

Cafeteria diet induces neuroplastic modifications in the nucleus accumbens mediated by microglia activation

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)

Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks

Backgound: Alcohol use disorder (AUD) is devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein-coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined. Methods: We tested Gpr88 knockout mice for alcohol-drinking and -seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity in naïve mice using resting-state functional magnetic resonance imaging. Results: Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise functional connectivity analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area, and amygdala connectional patterns. Also, effective connectivity from the ventral tegmental area to the nucleus accumbens and amygdala was reduced. Conclusions: Gpr88 deletion disrupts executive, reward, and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The functional connectivity signature is reminiscent of alterations observed in individuals at risk for AUD. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUD, and a potential drug target for AUD treatment.This work was supported by National Institutes of Health/National Institute of Drug Abuse Grant No. 05010 (to BLK); National Institute on Alcohol Abuse and Alcoholism Grant No. 16658 (to BLK); the Canada Fund for Innovation and the Canada Research Chairs (to BLK); Spanish Ministerio de Economía y Competitividad-MINECO Grant No. #SAF2014-59648-P/FEDER (to RM); Instituto de Salud Carlos III RETICS-RTA Grant No. RD12/0028/0023/FEDER (to RM); Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional sobre Drogas Grant No. PNSD-2013-068 (to RM); Generalitat de Catalunya AGAUR Grant No. 2014-SGR-1547 (to RM); a 2015 Catalan Institution for Research and Advanced Studies Academia Award (to RM); the Brazilian government's CAAP scholarship (Programa Ciência Sem Froteiras) (to SM-N); and the NeuroTime Erasmus+: Erasmus Mundus program of the European Commission. This publication/communication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein