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Nat Neurosci. 2014 Feb;17(2):254-61. doi: 10.1038/nn.3622. Epub 2014 Jan 12.

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

Author information

1
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [3] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [4] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
2
1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
3
Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA.
4
1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA. [4] Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
5
1] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA.
6
Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université de Strasbourg (UdS), Illkirch, France.
7
1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA.
8
1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA. [4] Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA. [5] Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

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.

PMID:
24413699
PMCID:
PMC4008330
DOI:
10.1038/nn.3622
[Indexed for MEDLINE]
Free PMC Article

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