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Alcohol use disorder (AUD) is characterized by problems controlling alcohol drinking despite adverse consequences, development of tolerance and/or withdrawal symptoms. Notably, sex differences in alcohol consumption patterns and susceptibility to relapse are well documented but remain poorly understood at the molecular level. In this study, we performed single-nuclei RNA sequencing (snRNA-seq) of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc) from male and female outbred RccHan Wistar rats exposed to the alcohol deprivation effect (ADE) paradigm, a well-established model of relapse-like drinking behaviour. Comparing high- to low-drinking rats, we found pronounced transcriptional changes across different cell types, with the highest number of differentially expressed genes observed in GABAergic medium spiny neurons (MSNs) of the NAcc and glutamatergic neurons of the mPFC associated with relapse. Importantly, we also identified sex- and region-dependent transcriptional alterations, including differential expression of dopamine receptors and phosphodiesterase family genes, which have previously been associated with AUD in humans, as well as alterations in the transcription of genes associated with synaptic plasticity and neuroimmune signalling. Finally, we found induction of immune-related genes in microglia and sex-dependent activation of immune- and myelination-related genes in astrocytes and oligodendrocytes. These findings highlight cell type-, region-, and sex-dependent molecular signatures associated with alcohol relapse drinking, which may provide new therapeutic targets for AUD. • Single nuclei RNA sequencing (snRNA-seq) of brain tissue from rats subjected to the alcohol deprivation effect (ADE) paradigm reveals cell type-, brain region-, and sex-dependent molecular signatures linked to alcohol relapse drinking. • Excessive alcohol consumption results in sex- and region-dependent dysregulation of dopamine receptor and phosphodiesterase gene expression in nucleus accumbens (NAcc) medium spiny neurons (MSNs) and medial prefrontal cortex (mPFC) glutamatergic neurons. • Alcohol relapse drinking induces sex- and region-dependent dysregulation of genes related to synaptic plasticity and neuronal injury in NAcc MSNs and mPFC glutamatergic neurons. • Glial populations exhibit immune activation in rats consuming high amounts of alcohol, with sex-dependent induction of immune- and myelination-related genes in astrocytes and oligodendrocytes.
Rigat et al. (Mon,) studied this question.