Advances in the treatment of alcohol use disorder

Targeting Acetylcholine Muscarinic Receptors to Treat AUD Leigh Walker Florey Department of Neuroscience and Mental Health, University of Melbourne, Australia Alcohol is the leading cause of death globally of people aged between 15-49 years. Despite this enormous socioeconomic burden, therapeutic treatment options for AUDs are limited and ineffective at a population level. A major hurdle in the development of new treatments is a lack of translation between preclinical animal models and efficacy in human subjects. We have recently begun to bridge this gap by concurrently examining human and rodent post-mortem samples. In this talk I will discuss our translationally relevant preclinical model of alcohol induced cholinergic dysfunction, and present recent findings from our laboratory highlighting the potential of muscarinic receptor modulation to reduce alcohol consumption and seeking.

Suppressing effect of KK-92A, a new positive allosteric modulator of the GABAB receptor, on different alcohol-motivated behaviors in alcohol-preferring rats Giancarlo Colombo Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato, Italy Treatment with the novel positive allosteric modulator (PAM) of the GABAB receptor, KK- 92A, has been reported to suppress several nicotine-motivated behaviors in rats [1]. The present study investigated whether the anti-addictive properties of KK-92A extend to alcohol. Acute treatment with non-sedative doses of KK-92A resulted in a dose-related suppression of (i) operant oral alcohol self- administration under fixed and progressive ratio schedules of reinforcement and (ii) cue-induced reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring rats. These data add KK-92A to the list of GABAB PAMs being effective in suppressing alcohol-motivated behaviors in rodent models of AUD [2]. [1] Li, X., Sturchler, E., Kaczanowska, K., Cameron, M., Finn, M.G., Griffin, P., McDonald, P., Markou, A. (2017). KK-92A, a novel GABAB receptor positive allosteric modulator, attenuates nicotine self-administration and cue-induced nicotine seeking in rats. Psychopharmacology, 234, 1633-1644. doi:10.1007/s00213-017-4594-9. [2] Maccioni, P., Colombo, G. (2019). Potential of GABAB receptor positive allosteric modulators in the treatment of alcohol use disorder. CNS Drugs, 33,107-123. doi: 10.1007/s40263-018-0596-3.

A Holistic Approach to Treatment of AUD Boris Tabakoff Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora CO, USA We designed and synthesized a new chemical entity (NCE) that would address targets thought to be important in the development of AUD. Receptor screening studies demonstrated an affinity of the compound for GABA-A receptors with little affinity for any of the other 50 receptors/ion channels/transporters. Electrophysiologic studies and mutational analysis demonstrated that our compound was a subunit selective positive allosteric agonist (PAM) at GABA-A receptors and acted through a novel binding site located at the ECD interface of α+/β- subunits [1]. The compound when given orally or i.p. could significantly reduce abstinence-induced alcohol consumption by alcohol dependent rats, but was found not to cross the blood/brain barrier. Further work indicated that the target of our drug may be the GABA receptors in the enteric nervous system and on immune system macrophages. Studies on the pharmacokinetics and toxicology of our compound are nearing completion. [1] Borghese, C. M., M. Herman, L. D. Snell, K. J. Lawrence, H. Y. Lee, D. S. Backos, L. A. Vanderlinden, R. A. Harris, M. Roberto, P. L. Hoffman and B. Tabakoff (2017). "Novel Molecule Exhibiting Selective Affinity for GABA(A) Receptor Subtypes." Sci Rep 7(1): 6230. doi: 10.1038/s41598-017-05966-x

Glycinergic agonists for treatment of AUD Bo Söderpalm Addiction Biology Unit, Section of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden We have identified strychnine-sensitive glycine receptors as key targets for ethanol in its dopamine releasing effect in the nucleus accumbens [1]. Local glycine perfusion or systemic administration of glycine uptake inhibitors enhances basal dopamine levels, prevents further dopamine release by ethanol and reduces ethanol intake in rats [1]. The response to glycinergic treatments appears, however, variable and further development of glycine uptake inhibitors for this indication is hindered by patent. We currently examine other means to activate glycine receptors by e.g. systemic administration of glycine and glycine analogues and to overcome response variability by exploring the possibility to interfere with mechanisms related to glycine receptor desensitization. We also explore if glycine agonists can be used as add-ons to other potential alcohol medications. [1] Soderpalm, B., Lidö HH, Ericson M. (2017). The Glycine Receptor-A Functionally Important Primary Brain Target of Ethanol. Alcohol Clin Exp Res, 41, 1816-1830. doi: 10.1111/acer.13483