Abstract
Studies suggest that the blockade of 5-HT1A, 5-HT7, and 5-HT3 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-HT1A and 5-HT7 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-HT3 receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT3 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-HT1A, 5-HT7, and 5-HT3 receptors might accelerate antidepressant response.
Highlights
Depression is a prevalent, highly debilitating mental disorder, in which exact neurobiological mechanisms remain unknown
We evaluated the effect of the active compound on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in murine hippocampus, and determined if the compounds interact with serotonin 5-HT3 receptors
HBK-15 at the concentrations 30, 100, and 300 nM decreased the maximal response by 24, 55, and 65%, respectively, which indicated a non-competitive interaction with 5HT3 receptors
Summary
Depression is a prevalent, highly debilitating mental disorder, in which exact neurobiological mechanisms remain unknown. Antidepressants, even those recently discovered, are effective in only half of the patients. Except for 5-HT5 receptor (which role in mood disorders is yet to be determined), most serotonin receptors take part in antidepressant-like response (for review, see Pytka et al [1]). The authors concluded that increasing serotonergic tone prior treatment with selective serotonin reuptake inhibitors might be more efficacious and even faster acting than current antidepressant therapies [10]. The scientists demonstrated that 1-week treatment with SB-269970 (a 5-HT7 receptor antagonist) caused behavioral, electrophysiological, and neuroanatomical changes that usually occur after longterm treatment with selective serotonin reuptake inhibitors [11]
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