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 β-
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.