Abstract
A major barrier to remission from an alcohol use disorder (AUD) is the continued risk of relapse during abstinence. Assessing the neuroadaptations after chronic alcohol and repeated abstinence is important to identify mechanisms that may contribute to relapse. In this study, we used a rhesus macaque model of long-term alcohol use and repeated abstinence, providing a platform to extend mechanistic findings from rodents to primates. The central amygdala (CeA) displays elevated GABA release following chronic alcohol in rodents and in abstinent male macaques, highlighting this neuroadaptation as a conserved mechanism that may underlie excessive alcohol consumption. Here, we determined circulating interleukin-1β (IL-1β) levels, CeA transcriptomic changes, and the effects of IL-1β and corticotropin releasing factor (CRF) signaling on CeA GABA transmission in male controls and abstinent drinkers. While no significant differences in peripheral IL-1β or the CeA transcriptome were observed, pathway analysis identified several canonical immune-related pathways. We addressed this potential dysregulation of CeA immune signaling in abstient drinkers with an electrophysiological approach. We found that IL-1β decreased CeA GABA release in controls while abstinent drinkers were less sensitive to IL-1β’s effects, suggesting adaptations in the neuromodulatory role of IL-1β. In contrast, CRF enhanced CeA GABA release similarly in controls and abstinent drinkers, consistent with rodent studies. Notably, CeA CRF expression was inversely correlated with intoxication, suggesting that CRF levels during abstinence may predict future intoxication. Together, our findings highlight conserved and divergent actions of chronic alcohol on neuroimmune and stress signaling on CeA GABA transmission across rodents and macaques.
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Acknowledgements
We thank Tim Carlson and Samuel Shin for their assistance and hospitality and Steven Gonzales for exceptional technical support and data processing. Short read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. This is manuscript number 30119 from The Scripps Research Institute. This research was supported in part by grants from the National Institutes of Health: INIA U01 AA013498 (MR), AA025408 (FPV), AA019431 (KAG), AA013641 (KAG), AA006420 (MR), AA15566 (MR), AA027700 (MR), AA021491 (MR) and INIA U01 AA013510 (KAG). The Oregon National Primate Research Center cores (Primate Genetics and Bioinformatics & Biostatistics) were supported by P51 OD011092 and P60 AA010760. The authors have no disclosures.
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RRP, FPV, MAH, KAG, and MR designed and conceived the project. KAG, VJ, NW and VCC generated macaque subjects for this study. RRP, FPV, and MAH collected electrophysiology data. RRP, FPV, MAH, MB and MR analyzed electrophysiology data. RA, LG, and SSF collected and analyzed the sequencing data. RRP, FPV, MR drafted the figures and manuscript. RRP, FPV, MAH, VJ, RA, MB, VCC, SSF, KAG, MR edited the manuscript.
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Patel, R.R., Varodayan, F.P., Herman, M.A. et al. Synaptic effects of IL-1β and CRF in the central amygdala after protracted alcohol abstinence in male rhesus macaques. Neuropsychopharmacol. 47, 847–856 (2022). https://doi.org/10.1038/s41386-021-01231-y
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DOI: https://doi.org/10.1038/s41386-021-01231-y
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