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

Bossert, J. M.; Mejias-Aponte, C. A.; Saunders, T. L.; Altidor, L. K.-P.; Emery, M. A.; Fredriksson, I.; Batista, A.; Claypool, S. M.; Caldwell, K. E.; Reiner, D. J.; Chow, J. J.; Foltz, M.; Kumar, V.; Seasholtz, A.; Hughes, E. D.; Filipiak, W. E.; Harvey, B. K.; Richie, C. T.; Vautier, F.; Gomez, J. L.; Michaelides, M.; Kieffer, B. L.; Watson, S. J.; Akil, H.; Shaham, Y.

doi:10.1101/2022.11.02.514895

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bioRxiv · 10.1101/2022.11.02.514895

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

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Abstract

The brain {micro}-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 anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the role of nucleus accumbens (NAc) MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and fluorescence in situ hybridization chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum (DS), and dorsal hippocampus, or MOR receptor density (except DS) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly co-expressed 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 and report sex-specific effects: 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 with these rats suggests a sex-specific role of NAc MOR-expressing cells in heroin self-administration. Significance statementThe brain {micro}-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 a potential sex-specific role of nucleus accumbens MOR-expressing cells in heroin self-administration. The new Oprm1-Cre rats can be used to study both the general and sex-specific role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

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Bossert, J. M., Mejias-Aponte, C. A., Saunders, T. L., Altidor, L. K.-P., Emery, M. A., Fredriksson, I., Batista, A., Claypool, S. M., Caldwell, K. E., Reiner, D. J., Chow, J. J., Foltz, M., Kumar, V., Seasholtz, A., Hughes, E. D., Filipiak, W. E., Harvey, B. K., Richie, C. T., Vautier, F., Gomez, J. L., Michaelides, M., Kieffer, B. L., Watson, S. J., Akil, H., Shaham, Y.. 2022-11-03. 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. https://doi.org/10.1101/2022.11.02.514895

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