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-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.

Single Administration of HBK-15—a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist—Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone

“…Since HBK-14 is stronger 5-HT 7 receptor antagonist, its anxiolytic-like effect might be more profound. These findings are consistent with our previous experiments, where we demonstrated that among the two, HBK-14 possessed stronger anxiolytic-like properties, whereas HBK-15 antidepressant-like activity [ 21 , 22 ]. The second explanation is simply the difference in bioavailability—HBK-14 has lower bioavailability, and this might underlie the lack of antidepressant-like effect.…”

“…Our previous experiments revealed that chronic treatment with HBK-15 increased serotonin level in the hippocampus [ 22 ]. Serotonin, at least partially, regulates the level of neurotrophins in the central nervous system [ 47 , 48 ].…”

“…The doses and route of administration of the studied compounds were based on our previous experiments [ 21 , 22 ]. Since antidepressant-like activity of HBK-14 and HBK-15 was due to the interaction with serotonergic (not adrenergic) system [ 21 ], we chose fluoxetine (selective serotonin reuptake inhibitor) as reference drug.…”

“…Although the compound moderately antagonized D 2 (IC 50 = 68 nM) and very weakly 5-HT 2A receptors (IC 50 = 4459 nM), it did not show antipsychotic-like or cataleptogenic properties (unpublished results). HBK-14 and HBK-15 presented negligible cholinolytic [ 22 ] and antihistaminic activities [ 23 ]. We proved that despite α 1 -adrenolytic properties [ 24 ], neither HBK-14 nor HBK-15 lowered blood pressure at antidepressant- and anxiolytic-like doses after chronic treatment [ 23 ].…”

“…Interestingly, unlike most antidepressants, the compound showed memory-enhancing properties and ameliorated memory deficits induced by scopolamine in mice [ 23 ]. Both compounds administered chronically increased serotonin levels in murine hippocampus [ 22 ].…”