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

Abstract

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.

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

“…In particular, acamprosate was found in previous studies to reduce the ADE (Spanagel et al, 1996a;Heyser et al, 1998;Lidö et al, 2012). As described in these previous studies, the calcium salt of N-acetylhomotaurinate (acamprosate) decreased the ADE in the present experiment.…”

“…In recent years, this model has become widely used for examining the efficacy of pharmacological agents in preventing compulsive alcohol consumption and relapse (Spanagel, 2009;Vengeliene et al, 2009). Moreover, acamprosate produces a reliable reduction of the ADE (Spanagel et al, 1996a;Heyser et al, 1998;Lidö et al, 2012). Critically, this effect is only observed if the calcium salt of Nacetylhomotaurinate or any other calcium salt is applied, which strongly suggests that the calcium counter ion of the acamprosate molecule is the biologically active species.…”

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…Based on previous reports (Achat-Mendes et al, 2012;Lido et al, 2012), Org 24598 (0.3, 1, and 3 mg/kg) was injected intraperitoneally with a volume of 5 ml/kg, 30 min before testing. d-amphetamine (1 mg/kg) was injected intraperitoneally with a volume of 5 ml/kg, 5 min before testing, based on evidence of improvement in probabilistic learning (Young, Khan and Powell; unpublished observations).…”

Astrocyte Function in Alcohol Reward and Addiction

“…Especially, glycine receptors could be important regulators of ethanol induced reinforcement as antagonists targeting glycine receptors both blocks the dopamine-elevating property of ethanol in vivo, as well as prevents ethanol-induced changes in striatal neurotransmission ex vivo [79,111,112]. In addition, inhibition of the glycine transporter GlyT1 persistently reduces ethanol intake and relapse-like alcohol drinking in rats [113][114][115][116], and might thus be a pharmacological target for the treatment of alcohol abuse disorders. However, even though it was recently shown that the GlyT1 transporter inhibitor Org25935 robustly reduces the number of days with heavy drinking, the effect was not significant as compared to placebo [117].…”