Abstract
Sphingosine-1-phosphate (S1P) is a lipid mediator signaling through broadly expressed G protein-coupled receptors. We found that S1P is regulated by alcohol and that S1P receptor agonists reduce alcohol drinking in rodent models. Specifically, we observed that two S1P receptor agonists FDA-approved for multiple sclerosis, fingolimod and ozanimod, and the more brain penetrant S1P (1) receptor agonist CYM5442, reduced binge alcohol drinking in the drinking in the dark (DID) paradigm in mice. CYM5442 also reduced drinking in dependent mice in the chronic intermittent ethanol vapor paradigm of dependence-induced increased drinking paired with 2 bottle-choice (CIE-2BC) as well as in non-dependent mice. CYM5442 reduced operant oral alcohol self-administration in both non-dependent and dependent rats made dependent by vapor exposure, and reduced motivation for alcohol in dependent rats tested in a progressive ratio schedule of reinforcement. CYM5442 significantly prevented cue-induced reinstatement in alcohol-dependent rats, a model of relapse to alcohol seeking. CYM5442 also reduced intake of non-drug reinforcers, including sucrose, food, water and, to a lesser extent, saccharine. Notably, CYM5442 was less aversive than naltrexone, an FDA-approved medication for the treatment of alcohol use disorder that shares a similar broad reducing action on alcohol intake and consummatory behavior. CYM5442 had no effect on loss of righting reflex, alcohol metabolism, motor coordination or spontaneous locomotor activity in rodents. Lastly, gene expression analysis by RNA-Seq revealed that S1P regulates a complex set of genes in the transition to alcohol dependence. Overall, our results establish S1P signaling as a novel therapeutic target for alcohol use disorder.