title: The novel non-imidazole histamine H3 receptor antagonist DL77 reduces voluntary alcohol intake and ethanol-induced conditioned place preference in mice.
abstract: It has become clear that histamine H3 receptors (H3R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H3R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 of 2.1 ± 0.2 mg/kg and pKi=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H3R antagonist, DL77 (0, 3, 10 and 30 mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10 mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H1R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H3R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism.
authors.affiliation: Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. Electronic address: amine.bahi@gmail.com.
authors.forename: Amine
authors.initials: A
authors.lastname: Bahi
authors.affiliation: Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Bassem
authors.initials: B
authors.lastname: Sadek
authors.affiliation: Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Syed M
authors.initials: SM
authors.lastname: Nurulain
authors.affiliation: Jagiellonian University-Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Łażewska
authors.affiliation: Jagiellonian University-Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9 St., 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000427:Alcohol Deterrents / Q000737:chemistry / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D002755:Choice Behavior / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology; D013037:Spatial Behavior / Q000187:drug effects; D055697:Taste Perception / Q000187:drug effects; D014836:Volition
chemical_list: C000608781:1-(3-(4-tert-pentylphenoxy)propyl)piperidine; D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D008761:Methylhistamines; D010647:Phenyl Ethers; D010880:Piperidines; D000431:Ethanol; C069357:alpha-methylhistamine; D011738:Pyrilamine
keywords: Conditioned place preference; Ethanol; Histamine H(3) receptor; Pyrilamine; R-(alpha)-methyl-histamine (RAMH); Two-bottle choice