Katarzyna Stachowicz

Polish Academy of Sciences, Warszawa, Masovian Voivodeship, Poland

Are you Katarzyna Stachowicz?

Claim your profile

Publications (54)171.43 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been shown that stressful events occurring in early life have a powerful influence on the development of the central nervous system. Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation and survival of both neurons and glial cells and is thought to exert antidepressant-like activity. Thus, it is possible that disturbances in the function of the IGF-1 system may be responsible for disturbances observed over the course of depression. Prenatal stress was used as a valid model of depression. Adult male offspring of control and stressed rat dams were subjected to behavioural testing (forced swim test). The level of IGF-1 in the blood and the expression of IGF-1, IGF-1R, IRS-1/2 in the hippocampus and frontal cortex using RT-PCR, ELISA and western blotting were measured. Additionally the effect of intracerebroventricularly administered IGF-1 and/or the IGF-1R receptor antagonist JB1 in the forced swim test was studied. Prenatally stressed rats showed depressive like behaviour, including increased immobility time as well as decreased mobility and climbing. Intracerebroventricular administration of IGF-1 reversed these effects in stressed animals, whereas concomitant administration of the IGF-1R antagonist JB1 completely blocked the effects. Biochemical analysis of homogenates from the hippocampus and frontal cortex revealed decreases in IGF-1 level and IGF-1R phosphorylation along with disturbances in IRS-1 phosphorylation. These findings reveal that prenatal stress alters IGF-1 signalling, which may contribute to the behavioural changes observed in depression.
    European Neuropsychopharmacology 09/2014; 24(9). DOI:10.1016/j.euroneuro.2014.07.002 · 5.40 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD). The aim of the present study was to investigate the possible role of the serotonergic system in the antidepressant-like activity of MTEP in the tail suspension test (TST) in C57BL/6J mice, using selected antagonists of serotonergic receptors and by applying two different methods of serotonin (5-HT) depletion. The results of our studies showed that the mGlu5 receptor antagonist, MTEP, similar to the fluoxetine used as reference AD, did not induce antidepressant-like effects in mice pretreated with tryptophan hydroxylase inhibitor, para-chlorophenylalanine. On the other hand, MTEP worked as a potential AD in the TST in mice fed on a tryptophan-free (TRP-free) diet for 3 weeks. However, fluoxetine, which was used as a reference control was also active in this experiment, suggesting that a TRP-free diet was not sufficiently effective in reducing the 5-HT level. Furthermore, we showed that the 5HT2A/2C antagonist, ritanserin, yet not the 5-HT1A antagonist, WAY100635, 5HT1B antagonist, SB224289 or 5HT4 antagonist, GR125487, reversed the antidepressant-like effects of MTEP in the TST. Finally, a sub-effective dose of MTEP co-administered with a sub-effective dose of citalopram induced an antidepressant-like effect in the TST in mice. The results of our studies suggest the involvement of serotonergic system activation in the antidepressant-like effects of the mGlu5 antagonist, MTEP, in the TST in mice.
    Psychopharmacology 08/2013; 231(1). DOI:10.1007/s00213-013-3206-6 · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: mGlu2/3 receptor agonists were shown to possess an antipsychotic-like potential in animal studies. Recent clinical investigations revealed that their antipsychotic potential might also manifest in humans. LY379268, the group II mGlu receptor orthosteric agonist, was previously shown to exhibit antipsychotic-like action in animal models of schizophrenia. However, the mechanism of its action is not fully recognized. Here, we decided to investigate the involvement of 5-HT1A receptors in the LY379268-induced antipsychotic effects. We used models of positive, negative and cognitive symptoms of schizophrenia, such as MK-801- and amphetamine-induced hyperactivity tests, DOI-induced head twitches, social interaction and novel object recognition. LY379268 was active in a wide range of doses (0.5-5mg/kg), depending on the paradigm. The effects of the drug were not antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg) in the models of positive and negative symptoms. Conversely, in the novel object recognition test, which exerts cognitive disturbances, the action of LY379268 was antagonized by WAY100635. Concomitantly, the action of a sub-effective dose of the drug was enhanced by the administration of a sub-effective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT. Altogether, we propose that the antipsychotic-like action of group II mGlu receptors' agonist is 5-HT1A independent in context of positive and negative symptoms, while the action towards cognitive disturbances seems to be 5-HT1A dependent.
    Behavioural brain research 08/2013; 256. DOI:10.1016/j.bbr.2013.08.007 · 3.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND AND PURPOSE: The aim of the study was to verify the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. EXPERIMENTAL APPROACH: The MK-801- and amphetamine-induced hyperactivities, as well as the 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitch tests in mouse were used as preclinical models for positive symptoms. MK-801-induced disruption of social interaction and spatial delayed alternation tests in rats were used as preclinical models for negative and cognitive symptoms of schizophrenia, respectively. KEY RESULTS: Lu AF21934 (0.1, 0.5, 1, 2 and 5 mg/kg) and Lu AF32615 (2, 5 and 10 mg/kg) dose-dependently inhibited both MK-801 and amphetamine-induced hyperactivity. The drugs antagonized DOI-induced head twitches and DOI-induced increased frequency of spontaneous excitatory postsynaptic currents (EPSCs). The specificity of Lu AF21934's effect was confirmed in mGlu4(-/-) mice, in which the compound did not antagonize DOI-induced head twitches. The MK-801-induced disruption in the social interaction test was abolished by Lu AF21934 at a dose of 0.5 mg/kg and Lu AF32615 at a dose of 10 mg/kg. In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg/kg, while Lu AF32615 was active at a dose of 10 mg/kg. CONCLUSIONS AND IMPLICATIONS: Altogether, we propose that activation of the mGlu4 receptor using positive allosteric modulators is a promising mechanism for the discovery of novel antipsychotic drugs.
    British Journal of Pharmacology 05/2013; 169(8). DOI:10.1111/bph.12254 · 4.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Twelve alkyl analogues (1-12) of the high-affinity serotonin transporter (SERT) inhibitor 6-nitroquipazine (6-NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki ). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three-dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and indicated that the octyl (8), decyl (10) and dodecyl (12) 6-NQ analogues exhibit moderate antidepressant activity.
    Chemical Biology &amp Drug Design 04/2013; 81(6). DOI:10.1111/cbdd.12116 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by (1)H NMR, (13)C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.
    European Journal of Medicinal Chemistry 03/2013; 63C:484-500. DOI:10.1016/j.ejmech.2013.02.033 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled 'mGluR'.
    Neuropharmacology 05/2012; 66. DOI:10.1016/j.neuropharm.2012.05.001 · 4.82 Impact Factor
  • European Neuropsychopharmacology 03/2012; 22:S44–S45. DOI:10.1016/S0924-977X(12)70047-0 · 5.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity. Here, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects. LSP1-2111 (1, 2, and 5 mg kg(-1)) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.). In contrast, AMN082 (3 and 6 mg kg(-1)) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates. Altogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.
    Psychopharmacology 09/2011; 220(3):481-94. DOI:10.1007/s00213-011-2502-2 · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Earlier studies have demonstrated that the agonists of the mGlu(2/3) receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu(2/3) receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1-5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu(2) receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5-5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABA(A) receptor antagonist flumazenil (10mg/kg) or GABA(B) receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT(1A) receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT(2A/2C) receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABA(A) receptors, presynaptic 5-HT(1A) and postsynaptic 5-HT(2A/2C) receptors is responsible for the phenomenon. This article is part of a Special Issue entitled 'Anxiety and Depression'.
    Neuropharmacology 08/2011; 62(1):322-31. DOI:10.1016/j.neuropharm.2011.07.042 · 4.82 Impact Factor
  • Source
    Anxiety Disorders, 08/2011; , ISBN: 978-953-307-592-1
  • [Show abstract] [Hide abstract]
    ABSTRACT: The synthesis, structure, in vitro and in vivo pharmacological activities of 3β-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3β position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.
    European Journal of Medicinal Chemistry 07/2011; 46(9):4474-88. DOI:10.1016/j.ejmech.2011.07.022 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the present study, we examined the anxiolytic-like effects of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a mGluR2/3 antagonist, in the Vogel conflict drinking test in rats. MGS0039 administered at the doses of 1 and 2 mg/kg ip (yet not at 3 mg/kg) produced anxiolytic-like effects in this test. Diazepam (2.5-10 mg/kg) was used as a reference drug. In the second part of our experiment, MGS0039 was tested at an effective dose of 2 mg/kg after a mixed injection with ritanserin (5-HT(2A/C) receptor antagonist) and WAY100635 (5-HT(1A) receptor antagonist) or flumazenil (benzodiazepine receptor antagonist), and all of the compounds were found to attenuate the effect of MGS0039. The above results indicate that the mGluR2/3 antagonist MGS0039 may play a role in the therapy of anxiety and that its action may be mediated by serotonin and the GABAergic systems.
    Pharmacological reports: PR 07/2011; 63(4):880-7. DOI:10.1016/S1734-1140(11)70603-X · 2.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Because zinc deficiency induces depression and anxiety-like behavior in rodents, we examined the effects of zinc administration in several tests by measuring anxiolytic activity in mice and rats. We now report that zinc significantly increased the number of entries into the open arms in the elevated plus maze in rats. Moreover, zinc treatment significantly increased the number of punished crossings in the four-plate test and attenuated stress-induced hyperthermia (SIH) in mice. However, no effect of zinc administration was observed in the elevated plus maze test in mice. This lack of effect in the latter case was probably due to the substantial zinc-induced reduction in locomotor activity by the doses used in mice. The present data demonstrate for the first time the anxiolytic-like activity of zinc in rodents and may indicate that zinc could be used as a novel therapeutic/adjunct agent in anxiolytic therapy.
    Pharmacological reports: PR 07/2011; 63(4):1050-5. DOI:10.1016/S1734-1140(11)70621-1 · 2.17 Impact Factor
  • Source
    Joanna Wieronska, Katarzyna Stachowicz, Andrzej Pilc
    06/2011; , ISBN: 978-953-307-592-1del
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, (1)H NMR, (13)C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 01/2011; 46(1):142-9. DOI:10.1016/j.ejmech.2010.10.026 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear. The aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated. The results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound. The results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs.
    Psychopharmacology 12/2010; 212(4):523-35. DOI:10.1007/s00213-010-1978-5 · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT(2A/C) receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111.
    Neuropharmacology 12/2010; 59(7-8):627-34. DOI:10.1016/j.neuropharm.2010.08.008 · 4.82 Impact Factor