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

@article{pmid36717230,

title = {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  Knock-in Rats},

author = {Jennifer M Bossert and Carlos A Mejias-Aponte and Thomas Saunders and Lindsay Altidor and Michael Emery and Ida Fredriksson and Ashley Batista and Sarah M Claypool and Kiera E Caldwell and David J Reiner and Jonathan J Chow and Matthew Foltz and Vivek Kumar and Audrey Seasholtz and Elizabeth Hughes and Wanda Filipiak and Brandon K Harvey and Christopher T Richie and Francois Vautier and Juan L Gomez and Michael Michaelides and Brigitte L Kieffer and Stanley J Watson and Huda Akil and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/36717230/},

doi = {10.1523/JNEUROSCI.2049-22.2023},

issn = {1529-2401},

year  = {2023},

date = {2023-03-01},

urldate = {2023-03-01},

journal = {J Neurosci},

volume = {43},

number = {10},

pages = {1692--1713},

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  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  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  expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between  knock-in rats and wildtype littermates. HCR-FISH assay showed that  is highly coexpressed with  (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  rats and had a stronger inhibitory effect on the effort to self-administer heroin in female  rats. The validation of an  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. 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  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  knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new  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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}