Dataset Information

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

ABSTRACT:

Background

Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.

Methods

We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food.

Results

Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures.

Conclusions

Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.

SUBMITTER: Charbogne P

PROVIDER: S-EPMC5386808 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

Charbogne Pauline P Gardon Olivier O Martín-García Elena E Keyworth Helen L HL Matsui Aya A Mechling Anna E AE Bienert Thomas T Nasseef Md Taufiq MT Robé Anne A Moquin Luc L Darcq Emmanuel E Ben Hamida Sami S Robledo Patricia P Matifas Audrey A Befort Katia K Gavériaux-Ruff Claire C Harsan Laura-Adela LA von Elverfeldt Dominik D Hennig Jurgen J Gratton Alain A Kitchen Ian I Bailey Alexis A Alvarez Veronica A VA Maldonado Rafael R Kieffer Brigitte L BL

Biological psychiatry 20161226 9

<h4>Background</h4>Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.<h4>Methods</h4>We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in ...[more]

PMID: 28185645

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Project description:BackgroundSynapse-associated proteins (SAPs) play important roles in central nervous system (CNS) tumors. Recent studies have reported that γ-aminobutyric acidergic (GABAergic) synapses also play critical roles in the development of gliomas. However, biomarkers of GABAergic synapses in low-grade gliomas (LGGs) have not yet been reported.MethodsmRNA data from normal brain tissue and gliomas were obtained from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, respectively. A validation dataset was also obtained from the Chinese Glioma Genome Atlas (CGGA) database. The expression patterns of GABAergic synapse-related genes (GSRGs) were evaluated with difference analysis in LGGs. Then, a GABAergic synapse-related risk signature (GSRS) was constructed with least absolute shrinkage and selection operator (LASSO) Cox regression analysis. According to the expression value and coefficients of identified GSRGs, the risk scores of all LGG samples were calculated. Univariate and multivariate Cox regression analyses were conducted to evaluate related risk scores for prognostic ability. Correlations between characteristics of the tumor microenvironment (TME) and risk scores were explored with single-sample gene set enrichment analysis (ssGSEA) and immunity profiles in LGGs. The GSRS-related pathways were investigated by gene set variation analysis (GSVA). Real-time PCR and the Human Protein Atlas (HPA) database were applied to explore related expression of hub genes selected in the GSRS.ResultsCompared with normal brain samples, 25 genes of 31 GSRGs were differentially expressed in LGG samples. A constructed five-gene GSRS was related to clinicopathological features and prognosis of LGGs by the LASSO algorithm. It was shown that the risk score level was positively related to the infiltrating level of native CD4 T cells and activated dendritic cells. GSVA identified several cancer-related pathways associated with the GSRS, such as P53 pathways and the JAK-STAT signaling pathway. Additionally, CA2, PTEN, OXTR, and SLC6A1 (hub genes identified in the GSRS) were regarded as the potential predictors in LGGs.ConclusionA new five-gene GSRS was identified and verified by bioinformatics methods. The GSRS provides a new perspective in LGG that may contribute to more accurate prediction of prognosis of LGGs.

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Dataset Information

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

Background

Methods

Results

Conclusions

Publications

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

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