Bidirectional sex-dependent regulation of alpha 6 and beta 3 nicotinic acetylcholine receptors by protein kinase C epsilon

摘要

Nicotine and alcohol are the most commonly abused substances worldwide and are frequently coabused. Nicotinic acetylcholine receptors (nAChRs) containing the alpha 6 and beta 3 subunits are expressed in neural reward circuits and are critical for nicotine and alcohol reward. nAChRs are dynamically regulated by signaling molecules such as protein kinase C epsilon (PKC epsilon), which impact transcription of alpha 6 and beta 3 subunit mRNA (Chrna6andChrnb3, respectively). Previous work found decreased expression ofChrna6andChrnb3transcripts in the ventral midbrain of male PKC epsilon(-/-)mice, who also consume less nicotine and alcohol compared with wild-type (WT) littermates. Using RT-qPCR, we show that female PKC epsilon(-/-)mice have higher expression ofChrna6andChrnb3transcripts in the ventral midbrain, which functionally impacts nAChR-dependent behavior as female but not male PKC epsilon(-/-)mice exhibit locomotor hypersensitivity to low-dose (0.25 mg/kg i.p.) nicotine. Female PKC epsilon(-/-)mice show no differences in alcohol-induced sedation in the loss-of-righting reflex assay (4.0 g/kg i.p.) compared with WT littermates, whereas male PKC epsilon(-/-)mice have enhanced sedation compared with WT mice. Female PKC epsilon(-/-)mice also show reduced immobility time in response to varenicline (1.0 mg/kg i.p.) compared with WT littermates in the tail suspension test, and this effect was absent in male mice. Additionally, we found that female PKC epsilon(-/-)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 epsilon, highlighting the importance of studying both sexes in preclinical animal models.