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Title: The cellular mechanisms underlying the fast antidepressant-like and procognitive effects of HBK-15


Depression is a severe mental condition, and according to the World Health Organization is now the second most common cause of disability in the world, and it will probably take the lead in 2030. Despite the high prevalence, reaching over 264 million people worldwide, we still do not have 100% effective treatment. Moreover, the drugs are still ineffective in around one-third of depressed individuals. One of the reasons for drug therapeutic failure may be low compliance and adherence – patients often discontinue therapy due to delayed onset of action of most antidepressants and many side effects, as well as the comorbidities. The depressed patients often suffer from cognitive disorders, that worsen the clinical course of the disease, increase the risk of relapse and the occurrence of residual symptoms. Unfortunately, despite their significance in depression, memory impairments are often overlooked when designing new drugs. Hence, there is an urgent need to find new antidepressants that will treat not only affective symptoms but also cognitive decline. Previous studies have shown that HBK-15 (1-[(2-chloro-6- methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride) possesses promising antidepressant-like activity in animal models of depression, reversing both behavioral and molecular changes. Additionally, this compound showed memory-enhancing proper ; ties and reversed scopolamine-induced cognitive deficits in rodents. Bearing the above in mind, this study aimed to discover the cellular mechanisms responsible for the antidepressant-like and procognitive activity of HBK-15, as well as to determine how the compound affects various types of memory and phases of memory formation. First, the affinity of HBK-15 to serotonin, dopamine, histamine, muscarinic, metabotropic, and ionotropic glutamate receptors as well as to dopamine, GABA and noradrenaline transporters was assessed to get a full receptor profile of the tested compound. Next, several rodent behavioral tests were used to investigate whether HBK-15 can reverse MK-801- induced deficits of various types of memory (recognition, emotional, motor, and spatial) at different stages of the learning processes (acquisition, consolidation, retrieval). Moreover, this study investigated the effect of a single administration of HBK-15 on the level of several neurotransmitters, including serotonin, dopamine, noradrenaline, acetylcholine, glutamate, gamma-aminobutyric acid, and histamine. The next research aim was to assess the antidepressant-like and procognitive activity of HBK-15 after a single administration in the unpredictable chronic mild stress model, as well as how long these pharmacological effects lasted. Furthermore, the explanation of the mechanism of action ; of HBK-15 included the investigation how HBK-15 affected the level of phosphorylated proteins: PKA, CaMKII, CaMKIV, RSK2, ERK1/2, PKC, CREB, BDNF using ELISA tests, and if the antidepressantlike and procognitive activity depended on the brain derived neurotrophic factor in BDNFVal/Met mice subjected to an unpredictable chronic mild stress procedure. HBK-15 possessed moderate to high affinity to serotonergic 5-HT2B and dopaminergic D1, D3, D4, and D5 receptors. Furthermore, HBK-15 reversed recognition, emotional, and spatial, but not motor, memory impairments associated with the impaired glutamatergic neurotransmission. Moreover, the tested compound showed procognitive activity at all stages of memory formation, i.e., acquisition, consolidation, and recall. Noteworthy, the single administration of HBK-15 was enough to produce the long-lasting antidepressant-like and procognitive effects (up to 24 h) in the animal model of depression. Moreover, HBK-15 normalized the decreased levels of p-CREB and BDNF in the hippocampus and in the prefrontal cortex of depressed animals, and this effect was mediated via ERK1/2, RSK2, CaMKIV, and PKA in the prefrontal cortex. Additionally, the procognitive, but not antidepressant-like activity, of HBK-15 is linked to the normal activity-dependent BDNF secretion. The obtained results suggest that HBK-15 may become a precursor for th ; e synthesis of new, fast-acting compounds with antidepressant-like and procognitive properties, that in the future, could be used in the treatment of depression with memory impairments.

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2 - studia doktoranckie

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farmakologia ; psychiatria

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Rada Dyscypliny Nauki farmaceutyczne


Pytka, Karolina

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Mar 25, 2024

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ZB-136282 Mar 25, 2024


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