Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

• Published in: Nature neuroscience Vol. 17; no. 2; pp. 254 - 261
• Main Authors: Cui, Yijun, Ostlund, Sean B, James, Alex S, Park, Chang Sin, Ge, Weihong, Roberts, Kristofer W, Mittal, Nitish, Murphy, Niall P, Cepeda, Carlos, Kieffer, Brigitte L, Levine, Michael S, Jentsch, James David, Walwyn, Wendy M, Sun, Yi E, Evans, Christopher J, Maidment, Nigel T, Yang, X William
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2014; Nature Publishing Group
• Subjects: 13/51; 14/19; 631/378/1689/5; 64/110; 64/60; Analysis of Variance; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biochemistry, Molecular Biology; Biological Techniques; Biomedicine; Brain research; Conditioning, Operant - drug effects; Conditioning, Operant - physiology; Corpus Striatum - cytology; Disease Models, Animal; Dopamine - metabolism; Drug abuse; Enkephalins - genetics; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Flow Cytometry; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Life Sciences; Mice; Mice, Transgenic; Microdialysis; Morphine - pharmacology; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics - pharmacology; Neural circuitry; Neural Pathways - physiology; Neurobiology; Neurons - classification; Neurons - drug effects; Neurons - physiology; Neurosciences; Opioids; Pain - drug therapy; Pain - genetics; Pain Measurement - drug effects; Physiological aspects; Protein Precursors - genetics; Receptors; Receptors, Opioid, mu - deficiency; Receptors, Opioid, mu - metabolism; Reward; Substance Withdrawal Syndrome - drug therapy
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3622

μ-opioid receptor (MOR) was previously shown to be necessary for opiate reward, analgesia and dependence. To better understand the specific anatomical and cell type loci of MOR action in opiate reward and reinforcement learning, the authors use cell-specific rescue expression of MOR in subtypes of neurons in the mouse brain that lack MOR globally and show that MOR in the striatal direct-pathway medium spiny neurons is sufficient to rescue the reward action of opioids without affecting opioid analgesia or withdrawal in MOR knockout mice.
μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued
MOR
transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function
in vivo
.