Potential of GABAB Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder
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The orthosteric γ-aminobutyric acidB (GABAB) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABAB PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABAB PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABAB PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABAB PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABAB PAMs on alcohol drinking and self-administration; (2) the efficacy of GABAB PAMs after intragastric administration; and (3) the ability of GABAB PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABAB PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABAB PAMs in AUD patients a feasible option.
The authors are grateful to Professor Federico Corelli for drawing Fig. 1, and Ms. Anne Farmer for language editing of this manuscript.
Compliance with Ethical Standards
The authors did not receive any specific grants for writing this paper.
Conflict of interest
Paola Maccioni and Giancarlo Colombo declare that they have no conflicts of interest relevant to the contents of this article.
Research involving animals
Data depicted in Fig. 1 were collected in an experiment that fully complied with European Directive no. 2010/63/EU and subsequent Italian Legislative Decree no. 26, 4 March 2014, on the ‘Protection of Animals Used for Scientific Purposes’.
- 11.Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, et al. Positive allosteric modulation of native and recombinant gamma-aminobutyric acidB receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol Pharmacol. 2001;60:963–71.CrossRefGoogle Scholar
- 12.Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, et al. N, N’-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function. J Pharmacol Exp Ther. 2003;307:322–30.CrossRefGoogle Scholar
- 28.Vengeliene V, Takahashi TT, Dravolina OA, Belozertseva I, Zvartau E, Bespalov AY, et al. Efficacy and side effects of baclofen and the novel GABAB receptor positive allosteric modulator CMPPE in animal models for alcohol and cocaine addiction. Psychopharmacology. 2018;235:1955–65.CrossRefGoogle Scholar
- 32.de Miguel E, Vekovischeva O, Kuokkanen K, Vesajoki M, Paasikoski N, Kaskinoro J, et al. GABAB receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine. Addict Biol. 2018. https://doi.org/10.1111/adb.12688 (Epub 13 Nov 2018).CrossRefPubMedGoogle Scholar
- 37.Maccioni P, Zaru A, Loi B, Lobina C, Carai MAM, Gessa GL, et al. Comparison of the effect of the GABAΒ receptor agonist, baclofen, and the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in 3 different lines of alcohol-preferring rats. Alcohol Clin Exp Res. 2012;36:1748–66.CrossRefGoogle Scholar
- 45.Maccioni P, Fantini N, Froestl W, Carai MAM, Gessa GL, Colombo G. Specific reduction of alcohol’s motivational properties by the positive allosteric modulator of the GABAB receptor, GS39783—comparison with the effect of the GABAB receptor direct agonist, baclofen. Alcohol Clin Exp Res. 2008;32:1558–64.CrossRefGoogle Scholar
- 47.Maccioni P, Flore P, Carai MAM, Mugnaini C, Pasquini S, Corelli F, et al. Reduction by the positive allosteric modulator of the GABAB receptor, GS39783, of alcohol self-administration in Sardinian alcohol-preferring rats exposed to the “sipper” procedure. Front Psychiatry. 2010;1:20.PubMedPubMedCentralGoogle Scholar
- 63.Leite-Morris KA, Kerestes HB, Colombo G. Intra-ventral tegmental area injection of the GABA B receptor positive allosteric modulator GS39783 inhibits ethanol seeking behavior in rats. Alcohol Clin Exp Res. 2009;33:226A.Google Scholar
- 64.Leite-Morris KA. Neurochemistry and neuropharmacology of the GABA-B receptor in a rodent model of alcohol binge drinking. Alcohol Clin Exp Res. 2013;37:255A.Google Scholar
- 68.Addex Therapeutics. ADX71441 in addiction. https://www.addextherapeutics.com/en/pipeline/researches/adx71441-addiction/. Accessed 20 Nov 2018.
- 69.ClinicalTrials.gov. Safety, tolerability, pharmacokinetics and pharmacodynamics of ODM-106 in healthy volunteers. https://clinicaltrials.gov/ct2/show/NCT02393950?term=NCT02393950&rank=1. Accessed 20 Nov 2018.