title: HBK-14 and HBK-15 with antidepressant-like and/or memory-enhancing properties increase serotonin levels in the hippocampus after chronic treatment in mice.
abstract: 5-HT1Aand 5-HT7receptor ligands might have antidepressant-like properties and improve cognitive function. We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT1Aand 5-HT7receptor antagonists in various behavioral tests in rodents. As a continuation of our previous experiments, in this study we aimed to investigate whether chronic administration of 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15) caused antidepressant-like effects and elevated serotonin levels in the murine hippocampus. We also evaluated cholinolytic properties and the influence of acute administration of both compounds on cognitive function in mice. To assess antidepressant-like properties and the influence on learning and memory we used forced swim test and step-through passive avoidance task in mice, respectively. Both compounds showed antidepressant-like properties and significantly elevated serotonin levels in the hippocampus after chronic treatment (HBK-14 - 2.5 mg/kg; HBK-15 - 0.625 and 1.25 mg/kg). HBK-15 administered chronically antidepressant-like activity at lower dose (0.625 mg/kg) than the dose active after acute treatment (1.25 mg/kg). None of the compounds affected locomotor activity of mice. HBK-15 possessed very weak cholinolytic properties, whereas HBK-14 did not show any effect on muscarinic receptors. Only HBK-15 (0.625 mg/kg) presented memory-enhancing properties and ameliorated cognitive impairments caused by scopolamine (1 mg/kg). Our results indicate that 5-HT1Aand 5-HT7antagonists might have potential in the treatment of depression and possess positive influence on cognitive function.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. karolina.pytka@uj.edu.pl.
authors.forename: Karolina
authors.identifier: 0000-0001-7134-9515
authors.initials: K
authors.lastname: Pytka
authors.affiliation: Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gawlik
authors.affiliation: Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Pawlica-Gosiewska
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Witalis
authors.affiliation: Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Waszkielewicz
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D018680:Cholinergic Antagonists; D005473:Fluoxetine; D018697:Nootropic Agents; D010647:Phenyl Ethers; D010879:Piperazines; D044282:Receptor, Serotonin, 5-HT1A; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C000620800:HBK-14; C000620801:HBK-15; C104425:serotonin 7 receptor
keywords: 2-methoxyphenylpiperazine derivative; 5-HT1A receptor antagonist; 5-HT7 receptor antagonist; Forced swim test; Mice; Step-through passive-avoidance test