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

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 Unexpectedly, Org25935 reduced both ethanol and water intake and induced strong CNS-depressive effects in AA-rats (withdrawn from further studies).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.

The Glycine Receptor—A Functionally Important Primary Brain Target of Ethanol

“…Further, Org25935 reversed a number of transcript alterations produced by long‐term EtOH consumption. Recently, Org25935 was examined also in genetically EtOH high‐consuming rats, the Finnish alcohol‐preferring rat strain (AA rats) (Lidö et al., ). These animals were, however, exceedingly sensitive to Org25935 and displayed a number of “side effects” that precluded adequate studying of EtOH intake.…”

“…However, DA levels need to increase rapidly in order to produce this effect (Volkow et al., ,b) and the DA elevations so far observed only in rats after glycine and GlyT inhibitors are slow and modest. Behavioral studies in rodents have failed to disclose rewarding properties of glycinergic drugs, rather the contrary, since GlyT‐1 inhibition reduces locomotor activity (Lidö et al., ) and is demonstrated to rather attenuate re‐acquisition of cocaine‐seeking behavior (Nic Dhonnchadha and Kantak, ). In humans, high‐dose glycine, GlyT inhibitors, and similar agents appear safe and with no signs of abuse liability (de Bejczy et al., ; Patel et al., ; Shim et al., ; Shoham et al., ; Yang and Svensson, ).…”

“…The visual events, most likely due to the high density of GlyRs in retina, were mild and resolved over time. The behavioral effects of concern when GlyT‐1 blockers were developed for treatment of schizophrenia were respiratory depression and motor deficits observed in rodents, rather than the abuse risk potential (Lidö et al., ; Mezler et al., ). In sum, glycine and glycinergic agents appear well tolerated and with minimal abuse liability.…”

“…This contrasts to findings with acamprosate (e.g., Lidö et al., ; Vengeliene et al., ) and naltrexone (e.g., Gardell et al., ; Korpi et al., ; Rezvani et al., ; Sable et al., ; Stromberg et al., ). Further, the GlyR, as compared to, for example, the GABA A receptor, appears robust in terms of receptor adaptations (Lidö et al., ). Together, these observations indicate that there should be little problems with dose escalation and withdrawal phenomena related to sustained and prolonged elevation of brain glycine levels.…”

Targeting Glycine Reuptake in Alcohol Seeking and Relapse

“…Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drug targets are warranted. The glycinergic system, because of its interaction with several alcohol-induced effects, is one of the tentative targets, and indeed, there is increasing evidence that targeting the glycinergic system may interfere with alcohol consumption and alcohol relapse Vengeliene et al, 2010;Lidö et al, 2012Lidö et al, , 2017. This is not surprising, as it is known that the activity of the dopaminergic reinforcement system is largely under the control of several neurotransmitter systems that are targeted by alcohol directly, including strychnine-sensitive glycine receptors (GlyRs) and N-methyl-D-aspartate receptors (NMDARs), which also have a glycine-binding site Vengeliene et al, 2008;Spanagel, 2009;Jonsson et al, 2014;Clarke et al, 2015;Söderpalm et al, 2017).…”