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

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 h 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 post-abstinent drinking phase as light (LD), binge (BD), heavy (HD) and very heavy (VHD drinkers). Comparing pre-ethanol to post-abstinent biopsies, four 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 × 10 −7 ) and plasma membrane changes (FDR < 1 × 10 −7 ). Genes in the immune response category included IL16 and 18 , CCR1 , B2M , TLR3 , 6 and 7 , SP2 and CX3CR1 . Upregulated genes ( N = 388) were particularly enriched in genes associated with the negative regulation of MAP kinase activity (FDR < 3 × 10 −5 ), including DUSP 1 , 4 , 5 , 6 and 18 , SPRY 2 , 3 , and 4 , SPRED2 , BMP4 and 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.