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Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects

Journal article
Authors Helga Lidö Höifödt
Susanne Jonsson
P. Hyytia
Mia Ericson
Bo Söderpalm
Published in Journal of Neural Transmission
Volume 124
Issue 5
Pages 607-619
ISSN 0300-9564
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 607-619
Language en
Links doi.org/10.1007/s00702-017-1685-z
Keywords Alcohol use disorder, Glycine, Glycine transporter-1 inhibitors, Ethanol intake, Wistar-rats, AA-rats, central-nervous-system, rat nucleus-accumbens, alcohol-preferring aa, glycine transporter, dopamine release, ethanol intake, org 25935, receptors, dependence, drinking, Neurosciences & Neurology
Subject categories Pharmacology, Neurochemistry

Abstract

The glycine transporter-1 inhibitor Org25935 is a promising candidate in a treatment concept for alcohol use disorder targeting the glycine system. Org25935 inhibits ethanol-induced dopamine elevation in brain reward regions and reduces ethanol intake in Wistar rats. This study aimed to further characterise the compound and used ethanol consumption, behavioral measures, and gene expression as parameters to investigate the effects in Wistar rats and, as pharmacogenetic comparison, Alko-Alcohol (AA) rats. Animals were provided limited access to ethanol in a two-bottle free-choice paradigm with daily drug administration. Acute effects of Org25935 were estimated using locomotor activity and neurobehavioral status. Effects on gene expression in Wistar rats were measured with qPCR. The higher but not the lower dose of Org25935 reduced alcohol intake in Wistar rats. Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies). Neurobehavioral effects by Org25935 differed between the strains (AA-rats towards sedation). Org25935 did not affect gene expression at the mRNA level in the glycine system of Wistar rats. The data indicate a small therapeutic range for the anti-alcohol properties of Org25935, a finding that may guide further evaluations of the clinical utility of GlyT-1 inhibitors. The results point to the importance of pharmacogenetic considerations when developing drugs for alcohol-related medical concerns. Despite the lack of successful clinical outcomes, to date, the heterogeneity of drug action of Org25935 and similar agents and the unmet medical need justify further studies of glycinergic compounds in alcohol use disorder.

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