PMID- 28550529 OWN - NLM STAT- MEDLINE DCOM- 20190226 LR - 20240322 IS - 1559-1182 (Electronic) IS - 0893-7648 (Print) IS - 0893-7648 (Linking) VI - 55 IP - 5 DP - 2018 May TI - Single Administration of HBK-15-a Triple 5-HT(1A), 5-HT(7), and 5-HT(3) Receptor Antagonist-Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone. PG - 3931-3945 LID - 10.1007/s12035-017-0605-4 [doi] AB - Studies suggest that the blockade of 5-HT(1A), 5-HT(7), and 5-HT(3) receptor may increase the speed of antidepressant response. 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), dual 5-HT(1A) and 5-HT(7) antagonists, showed significant antidepressant- and anxiolytic-like properties in our previous tests in rodents. In this study, we aimed to investigate their antidepressant potential using mouse model of corticosterone-induced depression. We chose sucrose preference test, forced swim test, and elevated plus maze to determine anhedonic-, antidepressant-, and anxiolytic-like activities. We also evaluated the influence of the active compound on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus. Moreover, for both compounds, we performed biofunctional (5-HT(3) receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT(3) receptor antagonists. HBK-14 (2.5 mg/kg) and HBK-15 (1.25 mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration permeated the blood-brain barrier with brain/plasma ratio lower than 1. The bioavailability of studied compounds after i.p. administration was 15% for HBK-14 and 54% for HBK-15. Chronic administration of HBK-15 (1.25 mg/kg) and fluoxetine (10 mg/kg) protected corticosterone-treated mice from anhedonic-, depressive-, and anxiety-like behaviors, as well as decreases in BDNF and NGF levels in the hippocampus. HBK-14 (2.5 mg/kg) counteracted anxiety-like behaviors in corticosterone-treated mice. Single administration of HBK-15 (1.25 mg/kg) and ketamine (1 mg/kg) reversed depression-like behavior and regulated decreased BDNF level in the hippocampus in corticosterone-treated mice. Our results suggest that simultaneous blockade of serotonergic 5-HT(1A), 5-HT(7), and 5-HT(3) receptors might accelerate antidepressant response. FAU - Pytka, Karolina AU - Pytka K AUID- ORCID: 0000-0001-7134-9515 AD - Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. karolina.pytka@uj.edu.pl. FAU - Gluch-Lutwin, Monika AU - Gluch-Lutwin M AD - Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. FAU - Kotanska, Magdalena AU - Kotanska M AD - Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. FAU - Waszkielewicz, Anna AU - Waszkielewicz A AD - Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. FAU - Kij, Agnieszka AU - Kij A AD - Chair and Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. AD - Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland. FAU - Walczak, Maria AU - Walczak M AD - Chair and Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland. AD - Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland. LA - eng GR - K/DSC/001955/Uniwersytet Jagiellonski Collegium Medicum/ GR - K/ZDS/006223/Uniwersytet Jagiellonski Collegium Medicum/ PT - Journal Article DEP - 20170526 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (HBK-14) RN - 0 (HBK-15) RN - 0 (Phenyl Ethers) RN - 0 (Piperazines) RN - 0 (Receptors, Serotonin) RN - 0 (Serotonin Antagonists) RN - 333DO1RDJY (Serotonin) RN - W980KJ009P (Corticosterone) SB - IM MH - Animals MH - *Behavior, Animal MH - Corticosterone MH - Depression/blood/*drug therapy MH - Disease Models, Animal MH - Guinea Pigs MH - Ileum/drug effects/physiology MH - Male MH - Mice MH - Muscle Contraction/drug effects MH - Phenyl Ethers/*administration & dosage/blood/chemistry/pharmacokinetics/pharmacology/*therapeutic use MH - Piperazines/*administration & dosage/blood/chemistry/pharmacokinetics/pharmacology/*therapeutic use MH - Receptors, Serotonin/*metabolism MH - Serotonin/pharmacology MH - Serotonin Antagonists/blood/chemistry/pharmacokinetics/*therapeutic use PMC - PMC5884906 OTO - NOTNLM OT - 5-HT1A receptor antagonist OT - 5-HT3 receptor antagonist OT - 5-HT7 receptor antagonist OT - Blood-brain barrier OT - CD-1 mice OT - Corticosterone-induced model of depression OT - Pharmacokinetics COIS- All experimental procedures were carried out in accordance with EU Directive 2010/63/EU and approved by the I Local Ethics Committee for Experiments on Animals of the Jagiellonian University in Krakow, Poland (approval numbers: 52/2014, 123/2015, 261/2015 and 104/2016). FUNDING: This study was supported by Jagiellonian University grant number K/DSC/001955 and partially by grant number K/ZDS/006223. EDAT- 2017/05/28 06:00 MHDA- 2019/02/27 06:00 PMCR- 2017/05/26 CRDT- 2017/05/28 06:00 PHST- 2017/02/14 00:00 [received] PHST- 2017/05/08 00:00 [accepted] PHST- 2017/05/28 06:00 [pubmed] PHST- 2019/02/27 06:00 [medline] PHST- 2017/05/28 06:00 [entrez] PHST- 2017/05/26 00:00 [pmc-release] AID - 10.1007/s12035-017-0605-4 [pii] AID - 605 [pii] AID - 10.1007/s12035-017-0605-4 [doi] PST - ppublish SO - Mol Neurobiol. 2018 May;55(5):3931-3945. doi: 10.1007/s12035-017-0605-4. Epub 2017 May 26.