PT  - JOURNAL ARTICLE
AU  - Jennifer M. Bossert
AU  - Carlos A. Mejias-Aponte
AU  - Thomas Saunders
AU  - Lindsay Altidor
AU  - Michael Emery
AU  - Ida Fredriksson
AU  - Ashley Batista
AU  - Sarah M. Claypool
AU  - Kiera E. Caldwell
AU  - David J. Reiner
AU  - Jonathan J. Chow
AU  - Matthew Foltz
AU  - Vivek Kumar
AU  - Audrey Seasholtz
AU  - Elizabeth Hughes
AU  - Wanda Filipiak
AU  - Brandon K. Harvey
AU  - Christopher T. Richie
AU  - Francois Vautier
AU  - Juan L. Gomez
AU  - Michael Michaelides
AU  - Brigitte L. Kieffer
AU  - Stanley J. Watson
AU  - Huda Akil
AU  - Yavin Shaham
TI  - 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 <em>Oprm1-Cre</em> Knock-in Rats
AID  - 10.1523/JNEUROSCI.2049-22.2023
DP  - 2023 Mar 08
TA  - The Journal of Neuroscience
PG  - 1692--1713
VI  - 43
IP  - 10
4099  - http://www.jneurosci.org/content/43/10/1692.short
4100  - http://www.jneurosci.org/content/43/10/1692.full
SO  - J. Neurosci.2023 Mar 08; 43
AB  - 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.