AUTHOR=Hitzemann Robert , Gao Lina , Fei Suzanne S. , Ray Karina , Vigh-Conrad Katinka A. , Phillips Tamara J. , Searles Robert , Cervera-Juanes Rita P. , Khadka Rupak , Carlson Timothy L. , Gonzales Steven W. , Newman Natali , Grant Kathleen A. 

TITLE=Effects of repeated alcohol abstinence on within-subject prefrontal cortical gene expression in rhesus macaques

JOURNAL=Advances in Drug and Alcohol Research

VOLUME=Volume 4 - 2024

YEAR=2024

URL=https://www.frontierspartnerships.org/journals/advances-in-drug-and-alcohol-research/articles/10.3389/adar.2024.12528

DOI=10.3389/adar.2024.12528

ISSN=2674-0001

ABSTRACT=Male rhesus monkeys (n=24) had a biopsy of prefrontal cortical area 46 prior to chronic ethanol self-administration (n=17) or caloric control (n=7). Fourteen months of daily self-administration (water vs 4% alcohol, 22 hr access/day termed "open-access") was followed by two cycles of prolonged abstinence (5 weeks) each followed by 3 months of open-access alcohol and a final abstinence followed by necropsy. At necropsy, a biopsy of Area 46, contralateral to the original biopsy, was obtained. Gene expression data (RNA-Seq) were collected comparing biopsy/necropsy samples. Monkeys were categorized by drinking status during the final postabstinent drinking phase as light (LD), binge (BD), heavy (HD) and very heavy (VHD drinkers). Comparing pre-ethanol to post-abstinent biopsies, 4 animals that converted from HD to VHD status had significant ontology enrichments in downregulated genes (necropsy minus biopsy n=286) that included immune response (FDR < 9 x 10 -7 ) and plasma membrane changes (FDR < 1 x 10 -7 ). Genes in the immune response category included IL16 & 18, CCR1, B2M, TLR3, 6 &7, SP2 & CX3CR1. Upregulated genes (N=388) were particularly enriched in genes associated with the negative regulation of MAP kinase activity (FDR < 3 x 10 -5 ), including DUSP 1,4,5, 6 & 18,  SPRY 2,3,& 4, SPRED2, BMP4 & RGS2.  Overall, these data illustrate the power of the NHP model and the within-subject design of genomic changes due to alcohol and suggest new targets for treating severe escalated drinking following repeated alcohol abstinence attempts.