The glycine reuptake inhibitor Org24598 and acamprosate reduce ethanol intake in the rat; tolerance development to acamprosate but not to Org24598

Extracellular glycine modulates accumbal dopamine levels as well as ethanol-induced dopamine overflow. Glycine availability is also crucial for regulating alcohol consumption and the glycine transporter 1 (GlyT-1) inhibitor Org25935 robustly decreases alcohol intake in rats. To explore whether the alcohol-intake reducing effect of Org25935 is substance bound, we examined the effect of a different selective GlyT-1 inhibitor, Org24598, on ethanol consumption in rats and compared the effect with that of acamprosate, a drug currently in clinical use. We studied the effects of daily Org24598 and acamprosate injections on male Wistar rats with 60% ethanol preference in a limited access two bottle free-choice model for 12 days, followed by alcohol deprivation for 14 days before a second test period of 10 days. Finally, rats underwent in vivo microdialysis where dopamine, glycine, taurine and beta-alanine in n. accumbens were measured. Org24598 profoundly reduced ethanol intake and the effect remained throughout both treatment periods. Acamprosate promptly reduced ethanol intake, but on the third day tolerance developed to this effect and acamprosate failed to influence alcohol consumption during the second test period. Neither Org24598 nor acamprosate reduced water intake. Following the drinking study, the Org24598 group displayed higher basal accumbal dopamine levels compared with acamprosate and vehicle groups. Both Org24598 and acamprosate reduced the ethanol-induced dopamine response in n. accumbens. The study demonstrates a robust anti-alcohol intake effect of the GlyT-1 inhibitor Org24598, supporting the new concept that GlyT-1 inhibition reduces ethanol consumption. GlyT-1 inhibition may represent a new treatment principle for alcoholism that is superior to acamprosate.