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Featured ArticleResearch Articles, Systems/Circuits

Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Oprm1-Cre Knock-in Rats

Jennifer M. Bossert, Carlos A. Mejias-Aponte, Thomas Saunders, Lindsay Altidor, Michael Emery, Ida Fredriksson, Ashley Batista, Sarah M. Claypool, Kiera E. Caldwell, David J. Reiner, Jonathan J. Chow, Matthew Foltz, Vivek Kumar, Audrey Seasholtz, Elizabeth Hughes, Wanda Filipiak, Brandon K. Harvey, Christopher T. Richie, Francois Vautier, Juan L. Gomez, Michael Michaelides, Brigitte L. Kieffer, Stanley J. Watson, Huda Akil and Yavin Shaham
Journal of Neuroscience 8 March 2023, 43 (10) 1692-1713; DOI: https://doi.org/10.1523/JNEUROSCI.2049-22.2023
Jennifer M. Bossert
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Carlos A. Mejias-Aponte
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Thomas Saunders
2University of Michigan, Ann Arbor, Michigan, 48104
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Lindsay Altidor
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Michael Emery
2University of Michigan, Ann Arbor, Michigan, 48104
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Ida Fredriksson
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Ashley Batista
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Sarah M. Claypool
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Kiera E. Caldwell
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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David J. Reiner
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Jonathan J. Chow
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Matthew Foltz
2University of Michigan, Ann Arbor, Michigan, 48104
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Vivek Kumar
2University of Michigan, Ann Arbor, Michigan, 48104
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Audrey Seasholtz
2University of Michigan, Ann Arbor, Michigan, 48104
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Elizabeth Hughes
2University of Michigan, Ann Arbor, Michigan, 48104
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Wanda Filipiak
2University of Michigan, Ann Arbor, Michigan, 48104
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Brandon K. Harvey
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Christopher T. Richie
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Francois Vautier
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Juan L. Gomez
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Michael Michaelides
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Brigitte L. Kieffer
3University of Strasbourg–Institut National de la Santé et de la Recherche Médicale U1114, Strasbourg, France, 67084
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Stanley J. Watson
2University of Michigan, Ann Arbor, Michigan, 48104
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Huda Akil
2University of Michigan, Ann Arbor, Michigan, 48104
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Yavin Shaham
1Intramural Research Program, National Institute on Drug Abuse–National Institutes of Health, Baltimore, Maryland, 21224
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Abstract

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the involvement of NAc MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly coexpressed with Oprm1 (95%-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an Oprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats.

SIGNIFICANCE STATEMENT The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new Oprm1-Cre rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

  • mu opioid receptor
  • knockin
  • CRISPR
  • heroin self-administration
  • pain
  • caspase 3 lesion

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The Journal of Neuroscience: 43 (10)
Journal of Neuroscience
Vol. 43, Issue 10
8 Mar 2023
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Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Oprm1-Cre Knock-in Rats
Jennifer M. Bossert, Carlos A. Mejias-Aponte, Thomas Saunders, Lindsay Altidor, Michael Emery, Ida Fredriksson, Ashley Batista, Sarah M. Claypool, Kiera E. Caldwell, David J. Reiner, Jonathan J. Chow, Matthew Foltz, Vivek Kumar, Audrey Seasholtz, Elizabeth Hughes, Wanda Filipiak, Brandon K. Harvey, Christopher T. Richie, Francois Vautier, Juan L. Gomez, Michael Michaelides, Brigitte L. Kieffer, Stanley J. Watson, Huda Akil, Yavin Shaham
Journal of Neuroscience 8 March 2023, 43 (10) 1692-1713; DOI: 10.1523/JNEUROSCI.2049-22.2023

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Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Oprm1-Cre Knock-in Rats
Jennifer M. Bossert, Carlos A. Mejias-Aponte, Thomas Saunders, Lindsay Altidor, Michael Emery, Ida Fredriksson, Ashley Batista, Sarah M. Claypool, Kiera E. Caldwell, David J. Reiner, Jonathan J. Chow, Matthew Foltz, Vivek Kumar, Audrey Seasholtz, Elizabeth Hughes, Wanda Filipiak, Brandon K. Harvey, Christopher T. Richie, Francois Vautier, Juan L. Gomez, Michael Michaelides, Brigitte L. Kieffer, Stanley J. Watson, Huda Akil, Yavin Shaham
Journal of Neuroscience 8 March 2023, 43 (10) 1692-1713; DOI: 10.1523/JNEUROSCI.2049-22.2023
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Keywords

  • mu opioid receptor
  • knockin
  • CRISPR
  • heroin self-administration
  • pain
  • caspase 3 lesion

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