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bioRxiv · 10.1101/2020.02.27.966978

Bidirectional sex-dependent regulation of α6 and β3 nicotinic acetylcholine receptors by protein kinase Cε

Moen, J. K.·DeBaker, M. C.·Myjack, J. E.·Wickman, K.·Lee, A. M.
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Abstract

Nicotine and alcohol are the most commonly abused substances worldwide, and comorbid nicotine and alcohol addiction is highly prevalent. Nicotinic acetylcholine receptors (nAChRs) containing the 6 and {beta}3 subunits are expressed in neural reward circuits and are critical for both nicotine and alcohol reward. nAChRs are dynamically regulated by signaling molecules such as protein kinase C epsilon (PKC{varepsilon}), which impact transcription of 6 and {beta}3 subunit mRNA (Chrna6 and Chrnb3, respectively). Previous work found decreased expression of Chrna6 and Chrnb3 transcripts in the ventral midbrain of male PKC{varepsilon}-/- mice, who also consume less nicotine and alcohol compared to wild-type (WT) littermates. Here, we show that female PKC{varepsilon}-/- mice have enhanced expression of Chrna6 and Chrnb3 transcripts in the ventral midbrain, which functionally impacts nAChR-dependent behavior, as female but not male PKC{varepsilon}-/- mice exhibit locomotor hypersensitivity to nicotine. Female PKC{varepsilon}-/- mice show no differences in alcohol-induced sedation compared to WT littermates, while male PKC{varepsilon}-/- have enhanced sedation compared to WT mice, a phenotype that has previously been reported in 6-/- mice. Female PKC{varepsilon}-/- mice also show reduced depression-like behavior in response to systemic injections of varenicline compared to WT littermates, and this effect was absent in male mice. Additionally, we found that female PKC{varepsilon}-/- mice show altered alcohol and nicotine consumption patterns in chronic voluntary two bottle choice assays. Our data reveal a bidirectional effect of sex in the transcriptional regulation of nicotinic receptors by PKC{varepsilon}, and highlight the importance of studying both sexes in preclinical animal models.

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Moen, J. K., DeBaker, M. C., Myjack, J. E., Wickman, K., Lee, A. M.. 2020-02-28. Bidirectional sex-dependent regulation of α6 and β3 nicotinic acetylcholine receptors by protein kinase Cε. https://doi.org/10.1101/2020.02.27.966978

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