RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1692
OP 1713
DO 10.1523/JNEUROSCI.2049-22.2023
VO 43
IS 10
A1 Bossert, Jennifer M.
A1 Mejias-Aponte, Carlos A.
A1 Saunders, Thomas
A1 Altidor, Lindsay
A1 Emery, Michael
A1 Fredriksson, Ida
A1 Batista, Ashley
A1 Claypool, Sarah M.
A1 Caldwell, Kiera E.
A1 Reiner, David J.
A1 Chow, Jonathan J.
A1 Foltz, Matthew
A1 Kumar, Vivek
A1 Seasholtz, Audrey
A1 Hughes, Elizabeth
A1 Filipiak, Wanda
A1 Harvey, Brandon K.
A1 Richie, Christopher T.
A1 Vautier, Francois
A1 Gomez, Juan L.
A1 Michaelides, Michael
A1 Kieffer, Brigitte L.
A1 Watson, Stanley J.
A1 Akil, Huda
A1 Shaham, Yavin
YR 2023
UL http://www.jneurosci.org/content/43/10/1692.abstract
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.