Back to Search
Start Over
Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food
- Source :
- Biological Psychiatry, Biological Psychiatry, 2017, 81 (9), pp.778-788. ⟨10.1016/j.biopsych.2016.12.022⟩, Recercat. Dipósit de la Recerca de Catalunya, instname, Biological Psychiatry, Elsevier, 2017, 81 (9), pp.778-788. ⟨10.1016/j.biopsych.2016.12.022⟩
- Publication Year :
- 2017
-
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. This work was supported by the Centre National de la Recherche Scientifique (BLK), Institut National de la Santé et de la Recherche Médicale (BK), Université de Strasbourg (BLK), Medical Research Council/Economic and Social Research Council interdisciplinary studentship (to HLK), the British Pharmacological Society (IK), the European Commission (Genaddict Grant No. LSHMCT2004-005166 to BLK), the U.S. National Institutes of Health (National Institute of Drug Addiction, Grant No. 05010 to BLK and National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658 to BLK), the Canada Fund for Innovation, and the Canada Research Chairs (to BLK). Electrophysiological experiments were funded by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to VAA) and Japan Society for Promotion of Science (to AMats). Self-administration studies were supported by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to RM), the Directorate-General for Research of the European Commission Framework Programme 7 (Grant No. HEALTH-2013-602891 to RM), the Spanish Redes Temáticas de Investigación Cooperativa en Salud-Instituto de Salud Carlos III (Grant No. RD12/0028/0023 to RM), the Spanish Ministerio de Economia y Competitividad (Grant No. SAF-2014-59648P to RM), the Plan Nacional Sobre Drogas (Grant No. PNSD-2013-5068 to RM), and the Catalan Government Agència de Gestió d'Ajuts Universitaris i de Recerca (Grant No. 2014-SGR-1547 to RM) and Institució Catalana de Recerca i Estudis Avançats-Acadèmia (Grant No. 2015 to RM). Part of the work was supported by German Research Foundation Excellence Cluster EXC-1086 BrainLinks-BrainTools (to JH).
- Subjects :
- 0301 basic medicine
Male
Narcotics
[SDV]Life Sciences [q-bio]
Dopamine
Conditioning, Classical
Receptors, Opioid, mu
Physical dependence
Striatum
Article
03 medical and health sciences
Mice
0302 clinical medicine
Prosencephalon
Opiate
Conditional gene knockout
Neural Pathways
mental disorders
medicine
Animals
GABAergic Neurons
ComputingMilieux_MISCELLANEOUS
Biological Psychiatry
Mice, Knockout
Motivation
Morphine
Ventral Tegmental Area
Feeding Behavior
Corpus Striatum
3. Good health
Mu opioid receptor
Ventral tegmental area
Heroin
030104 developmental biology
medicine.anatomical_structure
Inhibitory Postsynaptic Potentials
nervous system
Disinhibition
Forebrain
Female
μ-opioid receptor
medicine.symptom
Psychology
Neuroscience
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 18732402 and 00063223
- Database :
- OpenAIRE
- Journal :
- Biological Psychiatry, Biological Psychiatry, 2017, 81 (9), pp.778-788. ⟨10.1016/j.biopsych.2016.12.022⟩, Recercat. Dipósit de la Recerca de Catalunya, instname, Biological Psychiatry, Elsevier, 2017, 81 (9), pp.778-788. ⟨10.1016/j.biopsych.2016.12.022⟩
- Accession number :
- edsair.doi.dedup.....afd61bd192d132426f7e8e3c7fed3b86