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=4

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=<p>Male rhesus monkeys (<italic>n</italic> = 24) had a biopsy of prefrontal cortical area 46 prior to chronic ethanol self-administration (<italic>n</italic> = 17) or caloric control (<italic>n</italic> = 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 <italic>n</italic> = 286) that included immune response (FDR &lt; 9 × 10<sup>−7</sup>) and plasma membrane changes (FDR &lt; 1 × 10<sup>−7</sup>). Genes in the immune response category included <italic>IL16</italic> and <italic>18</italic>, <italic>CCR1</italic>, <italic>B2M</italic>, <italic>TLR3</italic>, <italic>6</italic> and <italic>7</italic>, <italic>SP2</italic> and <italic>CX3CR1</italic>. Upregulated genes (<italic>N</italic> = 388) were particularly enriched in genes associated with the negative regulation of MAP kinase activity (FDR &lt; 3 × 10<sup>−5</sup>), including <italic>DUSP 1</italic>, <italic>4</italic>, <italic>5</italic>, <italic>6</italic> and <italic>18</italic>, <italic>SPRY 2</italic>, <italic>3</italic>, and <italic>4</italic>, <italic>SPRED2</italic>, <italic>BMP4</italic> and <italic>RGS2</italic>. 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.</p>