DV Gil¹, C Ferguson², M Miskanic², SS Mrozowski², GE Homanics^2,3, SP Farris^2,4

Alcohol activates the neuroimmune system, triggering inflammatory signaling thought to promote alcohol consumption and contribute to alcohol use disorder (AUD). However, the molecular mechanisms linking neuroinflammation to drinking behavior remain unclear. Malat1 is a widely expressed, evolutionarily conserved long non-coding RNA that promotes pro-inflammatory signaling, including in the central nervous system. Malat1 is upregulated in post-mortem brains from AUD subjects and rodents chronically exposed to alcohol, yet its causal role in regulating alcohol consumption remains unexplored. We hypothesized that Malat1 promotes immune-induced increases in alcohol consumption. To assess whether modulation of Malat1-associated neuroinflammatory signaling alters alcohol intake, tamoxifen-inducible Malat1 homozygous floxed, hemizygous CreERT2 (Malat1 global KO) mice and Cre negative littermate controls (WT) underwent ten days of baseline two-bottle choice (2BC; 10% v/v), followed by ten additional days of drinking post-treatment. One cohort received a single lipopolysaccharide (LPS; 1 mg/kg, i.p.) injection to induce inflammation before this period; another received daily quercetin (30 mg/kg, i.p.), an anti-inflammatory compound reported to regulate Malat1 function and attenuate alcohol reward, prior to each post-treatment session. A subset of mice from each group was monitored with sipper devices to characterize temporal drinking patterns. LPS increased alcohol intake in females regardless of genotype. Quercetin produced a treatment-by-genotype interaction in females, suggesting Malat1 differentially modulates quercetin’s effects on drinking. Neither treatment altered male drinking, though Malat1 global KO males consistently consumed more alcohol than WT controls. Together, these findings suggest greater female sensitivity to inflammation-associated drinking, and a sex-specific role for Malat1 in mediating alcohol intake.

¹Center for Neuroscience at the University of Pittsburgh ²Department of Anesthesiology & Perioperative Medicine, ³Department of Pharmacology and Chemical Biology, ⁴Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA

Funding Support: NIAAA F31 AA032172, NIAAA U01 AA020889, NIAAA R01 AA030257