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

• Published in: Biological psychiatry (1969) Vol. 81; no. 9; pp. 778 - 788
• Main Authors: Charbogne, Pauline, Gardon, Olivier, Martín-García, Elena, Keyworth, Helen L, Matsui, Aya, Mechling, Anna E, Bienert, Thomas, Nasseef, Taufiq, Robé, Anne, Moquin, Luc, Darcq, Emmanuel, Ben Hamida, Sami, Robledo, Patricia, Matifas, Audrey, Befort, Katia, Gavériaux-Ruff, Claire, Harsan, Laura-Adela, von Elverfeldt, Dominik, Hennig, Jurgen, Gratton, Alain, Kitchen, Ian, Bailey, Alexis, Alvarez, Veronica A, Maldonado, Rafael, Kieffer, Brigitte L
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2017; Elsevier
• Subjects: Animals; Conditional gene knockout; Conditioning, Classical - drug effects; Conditioning, Classical - physiology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - physiology; Dopamine; Feeding Behavior - physiology; Female; GABAergic Neurons - metabolism; GABAergic Neurons - physiology; Heroin - administration & dosage; Inhibitory Postsynaptic Potentials - drug effects; Life Sciences; Male; Mice; Mice, Knockout; Morphine - administration & dosage; Motivation; Motivation - drug effects; Motivation - physiology; Mu opioid receptor; Narcotics - administration & dosage; Neural Pathways - physiology; Opiate; Prosencephalon - drug effects; Prosencephalon - metabolism; Prosencephalon - physiology; Psychiatry; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - physiology; Reward; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - physiology; Opiate; Dopamine; Mu opioid receptor; Reward; Motivation; Conditional gene knockout
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2016.12.022

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.