Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects.
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 Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies).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.
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. helga.lido@neuro.gu.se.|Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden. helga.lido@neuro.gu.se.
Helga Höifödt
0000-0002-7994-7904
HH
Lidö
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Susanne
S
Jonsson
Department of Pharmacology, University of Helsinki, Helsinki, Finland.
Petri
P
Hyytiä
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Mia
M
Ericson
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden.
Bo
B
Söderpalm
D000427:Alcohol Deterrents / Q000737:chemistry / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020022:Genetic Predisposition to Disease; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*
D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D050487:Glycine Plasma Membrane Transport Proteins; C520612:N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; C493266:Slc6a9 protein, rat; D013764:Tetrahydronaphthalenes; D000431:Ethanol
AA-rats; Alcohol use disorder; Ethanol intake; Glycine; Glycine transporter-1 inhibitors; Wistar-rats