Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats.
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.
Vengeliene
Valentina
V
Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. valentina.vengeliene@zi-mannheim.de
Leonardi-Essmann
Fernando
F
Sommer
Wolfgang H
WH
Marston
Hugh M
HM
Spanagel
Rainer
R
D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000235:genetics / Q000517:prevention & control*; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D055502:Secondary Prevention; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000427:Alcohol Deterrents; D050487:Glycine Plasma Membrane Transport Proteins; C520612:N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid; C493266:Slc6a9 protein, rat; D013764:Tetrahydronaphthalenes; D013654:Taurine; D000077443:Acamprosate