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Orexin receptor blockers: A tool for lowering alcohol intake and alcohol addictive behavior in the light of preclinical studies

Abstract Alcohol use disorder (AUD) is a severe and globally widespread neurological and psychiatric problem. The treatment with currently used drugs often does not bring the expected effect. New optimization methods or directions in pharmacotherapy are still being sought. The group of bioactive ligands, targeted at neuropeptides called orexins (OXs) and their receptors (OXRs), affects a number of functions including ingestion, sleep-wake regulation, as well as the brain reward system which is the basis of addiction. The purpose of this paper is to systematize the knowledge in the field of preclinical behavioral studies on rodents (rats and mice) in several models of alcohol consumption using the OXRs antagonists. The results of the experiments indicated a potential efficacy of particular OXRs antagonists in the AUD treatment, especially those selectively blocking the OX1R. Among them, SB-334867 in the lowest effective dose of 3 mg/kg i.p. was most studied, as shown in the model of two-bottle choice using C57BL/6 mice. Moreover, this compound did not affect the reduction of cognitive functions. GSK1059865 was also involved in the selective reduction of ethanol intake, and simultaneously did not alter the consumption of sugar solution. The other group of selective OX2R antagonists, such as TCS-OX2-29 and LSN2424100, was less efficient. In summary, the OX1R antagonists proved to have the potential in AUD therapy, not only through the reduction of ethanol consumption but also in the treatment of coexisting behavioral and physiological disorders, such as insomnia and anxiety.