Abstract
5-HT1A and 5-HT7 receptor ligands might have antidepressant-like properties and improve cognitive function. We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT1A and 5-HT7 receptor 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-HT1A and 5-HT7 antagonists might have potential in the treatment of depression and possess positive influence on cognitive function.
Highlights
Major depression affects millions of people worldwide and contributes to their disability
We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT1A and 5-HT7 receptor antagonists in various behavioral tests in rodents (Waszkielewicz et al 2015; Pytka et al 2015a)
In the present study we found that dual 5-HT1A and 5-HT7 antagonists i.e. HBK-14 and HBK-15 possessed antidepressant-like activity and increased serotonin levels in the hippocampus after chronic treatment
Summary
Major depression affects millions of people worldwide and contributes to their disability. Besides the well-defined depressive symptoms, patients often report cognitive disturbances, which significantly deteriorate their functioning. The scientists still search for the new compounds with increased efficacy and positive influence on cognition. Current antidepressants worsen (e.g. tricyclic antidepressants) or have no influence (e.g. selective serotonin reuptake inhibitors) on cognitive function (for review see: Biringer et al 2009). Some Authors suggested that reboxetine, bupropion, duloxetine or venlafaxine might have more beneficial effect on cognitive function than other antidepressants. Recent meta-analysis of clinical trials showed that only vortioxetine significantly improved cognition in depressed patients (McIntyre et al 2016). Positive influence on cognitive function was most likely due to the drug’s broad receptor profile.
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