Elsevier

Biological Psychiatry

Volume 68, Issue 8, 15 October 2010, Pages 704-711
Biological Psychiatry

Archival Report
Glycine Transporter-1 Blockade Leads to Persistently Reduced Relapse-like Alcohol Drinking in Rats

https://doi.org/10.1016/j.biopsych.2010.05.029Get rights and content

Background

Residual dysfunction of multiple neurotransmitter systems due to chronic alcohol use is likely responsible for the occurrence of compulsive alcohol seeking during abstinence and relapse behavior. There is increasing evidence that glycine, which activates both glycine and N-methyl-D-aspartate receptors, contributes to excessive alcohol consumption. We therefore hypothesized that the blockade of glycine transporter 1 might interfere with compulsive alcohol consumption and relapse behavior.

Methods

We used our animal model of alcoholism—long-term alcohol consumption with repeated deprivation phases in rats—to study the effects of a selective blocker of glycine transporter 1 Org25935. The abstinence-promoting drug acamprosate was used as a reference compound. Subsequently, we examined alterations in dorsal striatal gene expression caused by chronic ethanol (EtOH) consumption, focusing on glycinergic and glutamatergic signaling-related genes. Gene expression profiles of Org25935-treated EtOH-drinking rats were compared with vehicle-treated EtOH-drinking versus age-matched EtOH-naive rats.

Results

We found that repeated treatment with Org25935 reduced compulsive relapse-like drinking without the development of tolerance. Importantly, these antirelapse properties were maintained for at least 6 weeks in a treatment-free period. This persistent effect was paralleled by a reversal of altered expression levels of a set of glycinergic and glutamatergic signaling-related genes to the levels found in EtOH-naive control rats.

Conclusions

This study shows that treatment of rats with Org25935 leads to a reduction of compulsive alcohol consumption and relapse-like drinking behavior—an effect that persists into treatment-free periods. This long-term antirelapse effect might result from a restoration of normal glycinergic and glutamatergic signaling function.

Section snippets

Animals

Fifty-eight 2-month-old male Wistar rats (from our own breeding colony at the Central Institute of Mental Health, Mannheim, Germany) were used for the ADE and gene expression experiments. For further information, see Supplementary Methods and Materials in Supplement 1.

Long-Term Alcohol Self-Administration with Repeated Deprivation Phases

The long-term voluntary alcohol-drinking procedure excluding all deprivation phases lasted a total of 52 weeks (see Supplementary Methods and Materials in Supplement 1 for detailed information).

The pharmacological studies were

Effect of the Administration of Org25935 on ADE Measurements

Following the reintroduction of alcohol solutions after the eighth deprivation phase, the vehicle-treated group showed a typical increase in alcohol consumption, indicating the occurrence of an ADE (Figure 1A,B). This increase was not different from that observed during the first seven deprivation phases (data not shown). With respect to the pharmacological treatment, a two-way ANOVA for repeated measures revealed significantly different alcohol intake after a deprivation phase in all animal

Discussion

In the present study, we demonstrated that administration of the glycine transporter GlyT1 blocker Org25935 caused a significant dose-dependent reduction of relapse-like alcohol consumption in male Wistar rats. This effect was comparable with that seen in acamprosate-treated rats. Following both acamprosate and Org25935 treatment, water intake during ADE measurement was significantly increased, indicating the selectivity of these treatments toward alcohol consumption. However, the effect of the

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    Authors VV and FL-E contributed equally to this work.

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