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

Charbogne, P; Gardon, O; Martín-García, E; Keyworth, HL; Matsui, A; Mechling, AE; Bienert, T; Nasseef, T; Robé, A; Moquin, L; et al. Charbogne, P; Gardon, O; Martín-García, E; Keyworth, HL; Matsui, A; Mechling, AE; Bienert, T; Nasseef, T; Robé, A; Moquin, L; Darcq, E; Ben Hamida, S; Robledo, P; Matifas, A; Befort, K; Gavériaux-Ruff, C; Harsan, L-A; von Elverfeldt, D; Hennig, J; Gratton, A; Kitchen, I; Bailey, A; Alvarez, VA; Maldonado, R; Kieffer, BL (2017) Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food. Biol Psychiatry, 81 (9). pp. 778-788. ISSN 1873-2402 https://doi.org/10.1016/j.biopsych.2016.12.022
SGUL Authors: Bailey, Alexis

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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.

Item Type: Article
Additional Information: © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Conditional gene knockout, Dopamine, Motivation, Mu opioid receptor, Opiate, Reward, Conditional gene knockout, Dopamine, Motivation, Mu opioid receptor, Opiate, Reward, Psychiatry, 06 Biological Sciences, 17 Psychology And Cognitive Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Biol Psychiatry
ISSN: 1873-2402
Language: eng
Dates:
DateEvent
12 December 2016Accepted
26 December 2016Published Online
1 May 2017Published
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
PubMed ID: 28185645
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/108587
Publisher's version: https://doi.org/10.1016/j.biopsych.2016.12.022

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