The Experts below are selected from a list of 938490 Experts worldwide ranked by ideXlab platform

Michel Bourin - One of the best experts on this subject based on the ideXlab platform.

  • The Test reTest model of anxiety: An appraisal of findings to explain benzodiazepine tolerance.
    Pharmacology biochemistry and behavior, 2018
    Co-Authors: Michel Bourin
    Abstract:

    A Test reTest protocol in animal model of anxiety induces an increase of anxious behavior and a loss of benzodiazepine-induced effect. This effect, known as the "one trial tolerance", is mainly observed in the elevated plus maze, an ethological model of anxiety in mice, but also in the four plate Test, a model based on punishment. A review of some hypotheses based on behavioral, pharmacological and neurochemical approaches are proposed here to explain this benzodiazepines tolerance phenomenon.

  • Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the Four-Plate Test in Swiss mice
    Behavioural brain research, 2009
    Co-Authors: Michel Bourin, Martine Hascoët
    Abstract:

    Abstract Etifoxine is an anxiolytic compound structurally unrelated to benzodiazepine and neurosteroids but potentiating GABA A receptor function by a dual mode of action including a direct positive allosteric modulation through a site distinct from that of benzodiazepines. Etifoxine has been shown to possess some anxiolytic-like effects in rodents. Methods Using the Four-Plate Test (FPT) model of anxiety in mice the potential anxiolytic-like effect of etifoxine was first to re-evaluate. In a second part, in order to better understand the mechanism of action of etifoxine, interaction studies with 5-HT 2 ligands were performed in the FPT as mixed serotonergic and GABAergic mechanisms are highly implicated in the anxiolytic-like effect observed in the FPT. Results A dose response effect was observed for etifoxine from the dose of 40–100 mg/kg. Doses above to 60 mg/kg induced a sedative effect as was determined in the actimeter Test. The 5-HT 2A receptor antagonist SR 46349B blocked the anti-punishment activity of etifoxine (40 and 50 mg/kg), while the 5-HT 2B/2C receptor antagonist, SB 206553 and the 5-HT 2C receptor antagonist, RS 10-2221 did not alter its effects. In a same way, only the 5-HT 2A agonist DOI induced anti-punishment effect when co-administered with subthreshold doses of etifoxine. Conclusion The present results demonstrated that etifoxine effect was modulated by 5-HT 2A ligands co-administration. The large literature concerning GABA and 5-HT suggests that they could be co-released and could act as co-transmitters in some regions of the CNS and cross-communication between the two neurotransmitters might be an important modulator process of neuronal activity.

  • Brain structures implicated in the Four-Plate Test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI.
    Behavioural Brain Research, 2009
    Co-Authors: Benoit Petit-demouliere, Martine Hascoët, Fabienne Massé, Nicolas Cogrel, Michel Bourin
    Abstract:

    Abstract Four-Plate Test-reTest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to Four-Plate Test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naive and experienced mice: a benzodiazepine, diazepam that is only active in naive mice; and a 5-HT 2A/2C agonist, DOI that exert its anxiolytic-like effect both in naive and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naive and experienced mice. Diazepam had an anxiolytic-like effect in naive mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).

  • Temporal parameters of one-trial tolerance to benzodiazepines in Four-Plate Test-reTest.
    Behavioural Brain Research, 2007
    Co-Authors: Benoit Petit-demouliere, Michel Bourin
    Abstract:

    Anxiolytic-like effect of diazepam is abolished by a previous exposure to Four-Plate Test (FPT). Variations of temporal parameters: interval between trials and duration of Trial 1, with or without electric punishments allow characterizing factors which are responsible for this loss phenomenon. Complete spatial representation of FPT seems to be responsible of this one-trial tolerance, and needs at least a 30 s exposure to the apparatus to be completed, with or without punishments.

  • Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--reTest in mice.
    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2007
    Co-Authors: Benoit Petit-demouliere, Martine Hascoët, Michel Bourin
    Abstract:

    Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal Tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.

Tadeusz Librowski - One of the best experts on this subject based on the ideXlab platform.

  • Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents
    Neurotoxicity Research, 2017
    Co-Authors: Piotr Popik, Tadeusz Librowski, Gabriel Nowak, Małgorzata Hołuj, Kinga Sałat
    Abstract:

    The glutamate N -methyl- d -aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of Tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim Test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance Test and the rat novel object recognition Test. KET and TIL also reduced social behavior and accompanying 50-kHz “happy” ultrasonic vocalizations (USVs) in rats. TIL (5–15 mg/kg) displayed additional anxiolytic-like effects in the Four-Plate Test. Neither KET nor TIL affected pain response in the hot plate Test. Examination of the “side effects” revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod Test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile.

  • The anxiolytic-like activity of a novel N-cycloalkyl-N-benzoylpiperazine derivative
    Pharmacological Reports, 2016
    Co-Authors: Daniel Jan Strub, Tadeusz Librowski, Kinga Sałat, Stanisław Lochyński, Magdalena Gaweł, Adrian Podkowa
    Abstract:

    Background Anxiety-related disorders are among the most common mental illnesses in the world for which benzodiazepines, buspirone and antidepressant drugs remain the first-line treatment. These drugs have good efficacy but they have numerous disadvantages, such as drug abuse potential, delayed onset of action or tolerance. A literature review reveals that a variety of piperazine derivatives may exhibit interesting pharmacological properties, including anxiolytic-like, antidepressant, nootropic and antinociceptive activities demonstrated in animal models, as well as an antioxidant capacity shown in some in vitro Tests. Hence, the aim of this study was the synthesis and preliminary pharmacological in vivo evaluation of a novel N -cycloalkyl- N -benzoylpiperazine derivative, compound 9 . Methods The Test compound 9 was synthesized from a cyclic ketone 6,6-dimethylbicyclo[3.1.0]hexan-3-one (compound 7 ) and N -benzoylpiperazine. The final product was evaluated in vivo for its anxiolytic-like and antinociceptive activity after intraperitoneal ( ip ) administration. Its impact on animals’ locomotor activity and motor performance was also evaluated. Results At the dose of 50 mg/kg the Test compound 9 showed statistically significant ( p < 0.01) anxiolytic-like activity in the four plate Test. This effect was completely abolished by pretreatment with naloxone hydrochloride (1 mg/kg; ip ). Compound 9 did not influence animals’ locomotor activity or motor coordination. No antinociceptive effect was demonstrated in the hot plate Test. Conclusions The anxiolytic-like properties of N -bicyclo-[3.1.0]hexyl derivative ( 9 ) in the four plate Test are mediated by the opioid system. The results obtained make this compound a promising lead structure for further development of anxiolytic drugs.

  • The anxiolytic-like activity of a novel N-cycloalkyl-N-benzoylpiperazine derivative
    Pharmacological reports : PR, 2015
    Co-Authors: Daniel Strub, Tadeusz Librowski, Kinga Sałat, Stanisław Lochyński, Magdalena Gaweł, Adrian Podkowa
    Abstract:

    Abstract Background Anxiety-related disorders are among the most common mental illnesses in the world for which benzodiazepines, buspirone and antidepressant drugs remain the first-line treatment. These drugs have good efficacy but they have numerous disadvantages, such as drug abuse potential, delayed onset of action or tolerance. A literature review reveals that a variety of piperazine derivatives may exhibit interesting pharmacological properties, including anxiolytic-like, antidepressant, nootropic and antinociceptive activities demonstrated in animal models, as well as an antioxidant capacity shown in some in vitro Tests. Hence, the aim of this study was the synthesis and preliminary pharmacological in vivo evaluation of a novel N -cycloalkyl- N -benzoylpiperazine derivative, compound 9 . Methods The Test compound 9 was synthesized from a cyclic ketone 6,6-dimethylbicyclo[3.1.0]hexan-3-one (compound 7 ) and N -benzoylpiperazine. The final product was evaluated in vivo for its anxiolytic-like and antinociceptive activity after intraperitoneal ( ip ) administration. Its impact on animals’ locomotor activity and motor performance was also evaluated. Results At the dose of 50 mg/kg the Test compound 9 showed statistically significant ( p ip ). Compound 9 did not influence animals’ locomotor activity or motor coordination. No antinociceptive effect was demonstrated in the hot plate Test. Conclusions The anxiolytic-like properties of N -bicyclo-[3.1.0]hexyl derivative ( 9 ) in the four plate Test are mediated by the opioid system. The results obtained make this compound a promising lead structure for further development of anxiolytic drugs.

  • anticonvulsant active inhibitor of gaba transporter subtype 1 tiagabine with activity in mouse models of anxiety pain and depression
    Pharmacological Reports, 2015
    Co-Authors: Kinga Salat, Barbara Filipek, Adrian Podkowa, Anna Dziubina, Paula Kowalczyk, Katarzyna Kulig, Tadeusz Librowski
    Abstract:

    Abstract Background Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. Methods For pharmacological Tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral Tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate Test and the elevated plus maze Test. Antidepressant-like activity was assessed in the forced swim Test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals’ locomotor activity and motor coordination was investigated, too. Results Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100 mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% ( p Conclusions The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.

  • Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression
    Pharmacological Reports, 2015
    Co-Authors: Kinga Sałat, Barbara Filipek, Adrian Podkowa, Anna Dziubina, Paula Kowalczyk, Katarzyna Kulig, Tadeusz Librowski
    Abstract:

    Background Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. Methods For pharmacological Tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral Tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate Test and the elevated plus maze Test. Antidepressant-like activity was assessed in the forced swim Test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals’ locomotor activity and motor coordination was investigated, too. Results Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100 mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% ( p < 0.01), but it had no activity in the maximal electroshock seizure Test. Tiagabine showed anxiolytic-like and antidepressant-like effects. Although it apparently reduced animals’ nociceptive responses in pain Tests, these activities rather resulted from its sedative and motor-impairing properties demonstrated in the locomotor activity and the rotarod Tests, respectively. Conclusions The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.

Martine Hascoët - One of the best experts on this subject based on the ideXlab platform.

  • Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the Four-Plate Test in Swiss mice
    Behavioural brain research, 2009
    Co-Authors: Michel Bourin, Martine Hascoët
    Abstract:

    Abstract Etifoxine is an anxiolytic compound structurally unrelated to benzodiazepine and neurosteroids but potentiating GABA A receptor function by a dual mode of action including a direct positive allosteric modulation through a site distinct from that of benzodiazepines. Etifoxine has been shown to possess some anxiolytic-like effects in rodents. Methods Using the Four-Plate Test (FPT) model of anxiety in mice the potential anxiolytic-like effect of etifoxine was first to re-evaluate. In a second part, in order to better understand the mechanism of action of etifoxine, interaction studies with 5-HT 2 ligands were performed in the FPT as mixed serotonergic and GABAergic mechanisms are highly implicated in the anxiolytic-like effect observed in the FPT. Results A dose response effect was observed for etifoxine from the dose of 40–100 mg/kg. Doses above to 60 mg/kg induced a sedative effect as was determined in the actimeter Test. The 5-HT 2A receptor antagonist SR 46349B blocked the anti-punishment activity of etifoxine (40 and 50 mg/kg), while the 5-HT 2B/2C receptor antagonist, SB 206553 and the 5-HT 2C receptor antagonist, RS 10-2221 did not alter its effects. In a same way, only the 5-HT 2A agonist DOI induced anti-punishment effect when co-administered with subthreshold doses of etifoxine. Conclusion The present results demonstrated that etifoxine effect was modulated by 5-HT 2A ligands co-administration. The large literature concerning GABA and 5-HT suggests that they could be co-released and could act as co-transmitters in some regions of the CNS and cross-communication between the two neurotransmitters might be an important modulator process of neuronal activity.

  • Brain structures implicated in the Four-Plate Test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI.
    Behavioural Brain Research, 2009
    Co-Authors: Benoit Petit-demouliere, Martine Hascoët, Fabienne Massé, Nicolas Cogrel, Michel Bourin
    Abstract:

    Abstract Four-Plate Test-reTest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to Four-Plate Test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naive and experienced mice: a benzodiazepine, diazepam that is only active in naive mice; and a 5-HT 2A/2C agonist, DOI that exert its anxiolytic-like effect both in naive and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naive and experienced mice. Diazepam had an anxiolytic-like effect in naive mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).

  • Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--reTest in mice.
    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2007
    Co-Authors: Benoit Petit-demouliere, Martine Hascoët, Michel Bourin
    Abstract:

    Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal Tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.

  • Effect of GABAergic ligands on the anxiolytic-like activity of DOI (a 5-HT2A/2C agonist) in the Four-Plate Test in mice
    European Neuropsychopharmacology, 2006
    Co-Authors: Fabienne Massé, Martine Hascoët, Michel Bourin
    Abstract:

    Abstract 5-HTergic and GABAergic systems are involved in neurobiology of anxiety. Precedent studies have demonstrated that SSRIs possessed an anxiolytic-like effect in the Four-Plate Test (FPT) at doses that did not modify spontaneous locomotor activity. This effect seems to be mediated through the activation of 5-HT2A postsynaptic receptors. The purpose of the present study was to examine the implication of GABA system in the anxiolytic-like activity of DOI in the FPT. To achieve this, the co-administration of DOI (5-HT2A/2C receptor agonists) with GABAA and GABAB receptor ligands was evaluated in the FPT. Alprazolam, diazepam and muscimol (for higher dose) potentiated the anxiolytic-like effect of DOI. Bicuculline, picrotoxin and baclofen inhibited the anxiolytic-like effect of DOI. Flumazenil and CGP 35348 had no effect on the anxiolytic-like activity of DOI. These results suggest that the GABA system seems to be strongly implicated in the anxiolytic-like activity of DOI in the FPT.

  • Effect of GABAergic ligands on the anxiolytic-like activity of DOI (a 5-HT(2A/2C) agonist) in the Four-Plate Test in mice.
    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2006
    Co-Authors: Fabienne Massé, Martine Hascoët, Michel Bourin
    Abstract:

    5-HTergic and GABAergic systems are involved in neurobiology of anxiety. Precedent studies have demonstrated that SSRIs possessed an anxiolytic-like effect in the Four-Plate Test (FPT) at doses that did not modify spontaneous locomotor activity. This effect seems to be mediated through the activation of 5-HT(2A) postsynaptic receptors. The purpose of the present study was to examine the implication of GABA system in the anxiolytic-like activity of DOI in the FPT. To achieve this, the co-administration of DOI (5-HT(2A/2C) receptor agonists) with GABA(A) and GABA(B) receptor ligands was evaluated in the FPT. Alprazolam, diazepam and muscimol (for higher dose) potentiated the anxiolytic-like effect of DOI. Bicuculline, picrotoxin and baclofen inhibited the anxiolytic-like effect of DOI. Flumazenil and CGP 35348 had no effect on the anxiolytic-like activity of DOI. These results suggest that the GABA system seems to be strongly implicated in the anxiolytic-like activity of DOI in the FPT.

Kinga Sałat - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system.
    Bioorganic & medicinal chemistry letters, 2018
    Co-Authors: Katarzyna Pańczyk, Karolina Pytka, Anna Rapacz, Agata Siwek, Monika Głuch-lutwin, Kinga Sałat, Magdalena Jakubczyk, Anna Furgała, Anna Gryboś, Karolina Słoczyńska
    Abstract:

    Abstract Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim Test), locomotor, anxiolytic-like (Four-Plate Test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin Test, oxaliplatin Test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the Four-Plate Test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).

  • Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents
    Neurotoxicity Research, 2017
    Co-Authors: Piotr Popik, Tadeusz Librowski, Gabriel Nowak, Małgorzata Hołuj, Kinga Sałat
    Abstract:

    The glutamate N -methyl- d -aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of Tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim Test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance Test and the rat novel object recognition Test. KET and TIL also reduced social behavior and accompanying 50-kHz “happy” ultrasonic vocalizations (USVs) in rats. TIL (5–15 mg/kg) displayed additional anxiolytic-like effects in the Four-Plate Test. Neither KET nor TIL affected pain response in the hot plate Test. Examination of the “side effects” revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod Test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile.

  • Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one
    Pharmacological Reports, 2017
    Co-Authors: Katarzyna Malawska, Kinga Sałat, Aleksandra Rak, Beata Gryzło, Małgorzata Michałowska, Elżbieta Żmudzka, Krzysztof Lodarski, Barbara Malawska, Katarzyna Kulig
    Abstract:

    Background The aim of this study was to synthesize a series of new N -Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. Methods The target compounds 8–12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one ( 7 ) by a Mannich-type reaction. The obtained compounds were assessed and Tested for their anticonvulsant activity in two screening mouse models of seizures, i.e. , the maximal electroshock (MES) Test and in the subcutaneous pentylenetetrazole (scPTZ) Test. The effect of these compounds on animals’ motor coordination was measured in the rotarod Test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals’ locomotor activity was also evaluated. Results Compound 8 showed protection (25%) in the MES and in the scPTZ Tests at the dose of 100 mg/kg and was not neurotoxic. In the Four-Plate Test, compound 8 at the dose of 30 mg/kg showed a statistically significant ( p < 0.05) anxiolytic-like activity. In the forced swim Test, it reduced the immobility time by 24.3% (significant at p < 0.05), which indicates its potential antidepressant-like properties. In the locomotor activity Test, compound 8 significantly reduced animals’ locomotor activity by 79.9%. Conclusion The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) a promising lead structure for further development.

  • Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one.
    Pharmacological reports : PR, 2016
    Co-Authors: Katarzyna Malawska, Kinga Sałat, Aleksandra Rak, Beata Gryzło, Małgorzata Michałowska, Elżbieta Żmudzka, Krzysztof Lodarski, Barbara Malawska, Katarzyna Kulig
    Abstract:

    Abstract Background The aim of this study was to synthesize a series of new N -Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. Methods The target compounds 8–12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one ( 7 ) by a Mannich-type reaction. The obtained compounds were assessed and Tested for their anticonvulsant activity in two screening mouse models of seizures, i.e. , the maximal electroshock (MES) Test and in the subcutaneous pentylenetetrazole (scPTZ) Test. The effect of these compounds on animals’ motor coordination was measured in the rotarod Test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals’ locomotor activity was also evaluated. Results Compound 8 showed protection (25%) in the MES and in the scPTZ Tests at the dose of 100 mg/kg and was not neurotoxic. In the Four-Plate Test, compound 8 at the dose of 30 mg/kg showed a statistically significant ( p p  8 significantly reduced animals’ locomotor activity by 79.9%. Conclusion The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) a promising lead structure for further development.

  • The anxiolytic-like activity of a novel N-cycloalkyl-N-benzoylpiperazine derivative
    Pharmacological Reports, 2016
    Co-Authors: Daniel Jan Strub, Tadeusz Librowski, Kinga Sałat, Stanisław Lochyński, Magdalena Gaweł, Adrian Podkowa
    Abstract:

    Background Anxiety-related disorders are among the most common mental illnesses in the world for which benzodiazepines, buspirone and antidepressant drugs remain the first-line treatment. These drugs have good efficacy but they have numerous disadvantages, such as drug abuse potential, delayed onset of action or tolerance. A literature review reveals that a variety of piperazine derivatives may exhibit interesting pharmacological properties, including anxiolytic-like, antidepressant, nootropic and antinociceptive activities demonstrated in animal models, as well as an antioxidant capacity shown in some in vitro Tests. Hence, the aim of this study was the synthesis and preliminary pharmacological in vivo evaluation of a novel N -cycloalkyl- N -benzoylpiperazine derivative, compound 9 . Methods The Test compound 9 was synthesized from a cyclic ketone 6,6-dimethylbicyclo[3.1.0]hexan-3-one (compound 7 ) and N -benzoylpiperazine. The final product was evaluated in vivo for its anxiolytic-like and antinociceptive activity after intraperitoneal ( ip ) administration. Its impact on animals’ locomotor activity and motor performance was also evaluated. Results At the dose of 50 mg/kg the Test compound 9 showed statistically significant ( p < 0.01) anxiolytic-like activity in the four plate Test. This effect was completely abolished by pretreatment with naloxone hydrochloride (1 mg/kg; ip ). Compound 9 did not influence animals’ locomotor activity or motor coordination. No antinociceptive effect was demonstrated in the hot plate Test. Conclusions The anxiolytic-like properties of N -bicyclo-[3.1.0]hexyl derivative ( 9 ) in the four plate Test are mediated by the opioid system. The results obtained make this compound a promising lead structure for further development of anxiolytic drugs.

Katarzyna Kulig - One of the best experts on this subject based on the ideXlab platform.

  • Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one
    Pharmacological Reports, 2017
    Co-Authors: Katarzyna Malawska, Kinga Sałat, Aleksandra Rak, Beata Gryzło, Małgorzata Michałowska, Elżbieta Żmudzka, Krzysztof Lodarski, Barbara Malawska, Katarzyna Kulig
    Abstract:

    Background The aim of this study was to synthesize a series of new N -Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. Methods The target compounds 8–12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one ( 7 ) by a Mannich-type reaction. The obtained compounds were assessed and Tested for their anticonvulsant activity in two screening mouse models of seizures, i.e. , the maximal electroshock (MES) Test and in the subcutaneous pentylenetetrazole (scPTZ) Test. The effect of these compounds on animals’ motor coordination was measured in the rotarod Test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals’ locomotor activity was also evaluated. Results Compound 8 showed protection (25%) in the MES and in the scPTZ Tests at the dose of 100 mg/kg and was not neurotoxic. In the Four-Plate Test, compound 8 at the dose of 30 mg/kg showed a statistically significant ( p < 0.05) anxiolytic-like activity. In the forced swim Test, it reduced the immobility time by 24.3% (significant at p < 0.05), which indicates its potential antidepressant-like properties. In the locomotor activity Test, compound 8 significantly reduced animals’ locomotor activity by 79.9%. Conclusion The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) a promising lead structure for further development.

  • Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one.
    Pharmacological reports : PR, 2016
    Co-Authors: Katarzyna Malawska, Kinga Sałat, Aleksandra Rak, Beata Gryzło, Małgorzata Michałowska, Elżbieta Żmudzka, Krzysztof Lodarski, Barbara Malawska, Katarzyna Kulig
    Abstract:

    Abstract Background The aim of this study was to synthesize a series of new N -Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. Methods The target compounds 8–12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one ( 7 ) by a Mannich-type reaction. The obtained compounds were assessed and Tested for their anticonvulsant activity in two screening mouse models of seizures, i.e. , the maximal electroshock (MES) Test and in the subcutaneous pentylenetetrazole (scPTZ) Test. The effect of these compounds on animals’ motor coordination was measured in the rotarod Test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals’ locomotor activity was also evaluated. Results Compound 8 showed protection (25%) in the MES and in the scPTZ Tests at the dose of 100 mg/kg and was not neurotoxic. In the Four-Plate Test, compound 8 at the dose of 30 mg/kg showed a statistically significant ( p p  8 significantly reduced animals’ locomotor activity by 79.9%. Conclusion The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one ( 8 ) a promising lead structure for further development.

  • anticonvulsant active inhibitor of gaba transporter subtype 1 tiagabine with activity in mouse models of anxiety pain and depression
    Pharmacological Reports, 2015
    Co-Authors: Kinga Salat, Barbara Filipek, Adrian Podkowa, Anna Dziubina, Paula Kowalczyk, Katarzyna Kulig, Tadeusz Librowski
    Abstract:

    Abstract Background Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. Methods For pharmacological Tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral Tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate Test and the elevated plus maze Test. Antidepressant-like activity was assessed in the forced swim Test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals’ locomotor activity and motor coordination was investigated, too. Results Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100 mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% ( p Conclusions The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.

  • Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression
    Pharmacological Reports, 2015
    Co-Authors: Kinga Sałat, Barbara Filipek, Adrian Podkowa, Anna Dziubina, Paula Kowalczyk, Katarzyna Kulig, Tadeusz Librowski
    Abstract:

    Background Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. Methods For pharmacological Tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral Tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate Test and the elevated plus maze Test. Antidepressant-like activity was assessed in the forced swim Test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals’ locomotor activity and motor coordination was investigated, too. Results Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100 mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% ( p < 0.01), but it had no activity in the maximal electroshock seizure Test. Tiagabine showed anxiolytic-like and antidepressant-like effects. Although it apparently reduced animals’ nociceptive responses in pain Tests, these activities rather resulted from its sedative and motor-impairing properties demonstrated in the locomotor activity and the rotarod Tests, respectively. Conclusions The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.

  • Synthesis and pharmacological properties of new GABA uptake inhibitors
    Pharmacological Reports, 2012
    Co-Authors: Kinga Sałat, Barbara Filipek, Barbara Malawska, Anna Więckowska, Krzysztof Więckowski, Georg C. Höfner, Jacek Kamiński, Klaus T. Wanner, Katarzyna Kulig
    Abstract:

    Background γ-Aminobutanoic acid (GABA) is the principal inhibitory neurotransmitter in the mammalian central nervous system. The identification and subsequent development of the GABA transport inhibitors which enhance the GABA-ergic transmission has shown the important role that GABA transporters play in the control of numerous functions of the nervous system. Compounds which inhibit GABA uptake are used as antiepileptic drugs (tiagabine - a selective GAT1 inhibitor), they are also being investigated for other indications, including treatment of psychosis, general anxiety, sleep disorders, drug addiction or acute and chronic pain. Methods In this paper, the synthesis of 2-substituted-4-(1,3-dioxoisoindolin-2-ylo)-butanamides and 2-substituted-4-amino-butanoic acids derivatives is described. These compounds were Tested in vitro for their ability to inhibit GABA uptake. The inhibitory potency towards murine plasma membrane GABA transporters (mGAT1-4) was performed as [^3H]GABA uptake assay based on stably transfected HEK cells. Compound 18 , which demonstrated the highest affinity for mGAT1-4 (pIC50 ranged from 4.42 for mGAT1 to 5.07 for mGAT3), was additionally investigated in several behavioral Tests in mice. Results Compound 18 increased the locomotor activity (14-38%) and had anxiolytic-like properties in the Four-Plate Test (ED50 = 9.3 mg/kg). It did not show analgesic activity in acute pain model, namely the hot plate Test, however, it was antinociceptive in the acetic acid-induced writhing Test (ED50 =15.3 mg/kg) and in the formalin model of tonic pain. In the latter assay, it diminished no-cifensive behavior in both phases and in the first (neurogenic) phase of this Test the obtained ED50 value (5.3 mg/kg) was similar to morphine (3.0 mg/kg). Conclusion Compound 18 exhibited significant anxiolytic-like properties and was antinociceptive in some models of pain in mice. Moreover, it did not impair animals’ motor coordination in the chimney Test. Some of the described pharmacological activities of compound 18 can be partly explained based on its affinity for plasma membrane GABA transporters.