The Experts below are selected from a list of 28809 Experts worldwide ranked by ideXlab platform
Hong-seork Choi - One of the best experts on this subject based on the ideXlab platform.
-
NMDA Receptor Antagonists enhance 5-HT_2 Receptor-mediated behavior, head-twitch response, in PCPA-treated mice
Archives of Pharmacal Research, 1999Co-Authors: Insook Park, Hong-seork ChoiAbstract:Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) Receptor Antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA Receptors in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT_2 Receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic Receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti- tive (MK-801, ketamine, dextrorphan and dextromethorphan) NMDA Receptor Antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p -chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA Receptor in 5-HT-induced HTR at the postsynaptic 5-HT_2 Receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA Receptor antagonist, NMDA and a serotonin 5-HT_2 Receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA Receptors play an important role in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT_2 Receptors.
-
NMDA Receptor Antagonists enhance 5 ht2 Receptor mediated behavior head twitch response in pcpa treated mice
Archives of Pharmacal Research, 1999Co-Authors: Insook Park, Hong-seork ChoiAbstract:Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) Receptor Antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA Receptors in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 Receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic Receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti- tive (MK-801, ketamine, dextrorphan and dextromethorphan) NMDA Receptor Antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, inp-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA Receptor in 5-HT-induced HTR at the postsynaptic 5-HT2 Receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA Receptor antagonist, NMDA and a serotonin 5-HT2 Receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA Receptors play an important role in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 Receptors.
Insook Park - One of the best experts on this subject based on the ideXlab platform.
-
NMDA Receptor Antagonists enhance 5 ht2 Receptor mediated behavior head twitch response in pcpa treated mice
Archives of Pharmacal Research, 1999Co-Authors: Insook Park, Hong-seork ChoiAbstract:Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) Receptor Antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA Receptors in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 Receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic Receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti- tive (MK-801, ketamine, dextrorphan and dextromethorphan) NMDA Receptor Antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, inp-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA Receptor in 5-HT-induced HTR at the postsynaptic 5-HT2 Receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA Receptor antagonist, NMDA and a serotonin 5-HT2 Receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA Receptors play an important role in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 Receptors.
-
NMDA Receptor Antagonists enhance 5-HT_2 Receptor-mediated behavior, head-twitch response, in PCPA-treated mice
Archives of Pharmacal Research, 1999Co-Authors: Insook Park, Hong-seork ChoiAbstract:Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) Receptor Antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA Receptors in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT_2 Receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic Receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti- tive (MK-801, ketamine, dextrorphan and dextromethorphan) NMDA Receptor Antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p -chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA Receptor in 5-HT-induced HTR at the postsynaptic 5-HT_2 Receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA Receptor antagonist, NMDA and a serotonin 5-HT_2 Receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA Receptors play an important role in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT_2 Receptors.
-
NMDA Receptor Antagonists enhance 5 ht2 Receptor mediated behavior head twitch response in mice
Life Sciences, 1998Co-Authors: Insook Park, Wookyu ParkAbstract:The purpose of this study was to characterize behavioral interactions between glutamatergic and serotonergic 5-HT2 Receptors. Both competitive (AP-5 [D-2-amino-5-phosphovalerate] and D-CPP [3-(2carboxypiperazine-4yl)-propylphosphonate]) and noncompetitive (MK-801 [dizocilpine], ketamine, dextrorphan and dextromethorphan) N-methyl-D-aspartate (NMDA) Receptor Antagonists markedly enhanced a selective serotonergic behavior, the head twitch response (HTR), in mice. In contrast, NMDA itself inhibited 5-hydroxytryptamine (5-HT)-induced HTR in mice. These results suggest that glutamatergic neurotransmission may modulate serotonergic function at the 5-HT2 Receptor.
Wojciech Danysz - One of the best experts on this subject based on the ideXlab platform.
-
synergistic effect of uncompetitive NMDA Receptor Antagonists and antidepressant drugs in the forced swimming test in rats
Neuropharmacology, 2002Co-Authors: Z Rogoz, G Skuza, J Maj, Wojciech DanyszAbstract:In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA Receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA Receptor Antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA Receptor Antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.
-
Uncompetitive NMDA Receptor Antagonists potentiate morphine antinociception recorded from the tail but not from the hind paw in rats.
European Journal of Pharmacology, 2001Co-Authors: E Kozela, Wojciech Danysz, P PopikAbstract:Abstract We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA Receptor Antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mg/kg, respectively. These doses were used in further experiments. Thirty minutes before morphine, rats were administered the NMDA Receptor Antagonists dextromethorphan (2.5–30 mg/kg), memantine (2.5–15 mg/kg) and MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) (1.25–10 mg/kg). All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA Receptor Antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA Receptor Antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws.
-
Clinically available NMDA Receptor Antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000Co-Authors: P Popik, E Kozela, Wojciech DanyszAbstract:The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-d-aspartate (NMDA) Receptor Antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA Receptor Antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5–10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA Receptor antagonist+vehicle, vehicle+morphine or NMDA Receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA Antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA Receptor Antagonists may be used to inhibit ongoing morphine tolerance.
-
memantine and the amino alkyl cyclohexane mrz 2 579 are moderate affinity uncompetitive NMDA Receptor Antagonists in vitro characterisation
Amino Acids, 2000Co-Authors: Chris G Parsons, Wojciech Danysz, Günter QuackAbstract:There is general agreement that moderate affinity uncompetitive NMDA Receptor Antagonists combine good efficacy and tolerability in animal models of disturbances in glutamatergic transmission. There are several theories on which properties are important for this profile including 1, rapid access to the channel at the start of pathological overactivity 2, rapid, voltage-dependent relief of blockade during physiological synaptic activation and 3, partial untrapping. Merz has developed a series of novel uncompetitive NMDA Receptor Antagonists based on the cyclohexane structure. In cultured hippocampal neurones MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane) shows similar blocking kinetics to memantine (Kon 10.7 * 104 M−1 sec−1, Koff 0.20 sec−1 at −70 mV) and binds at the same depth in the NMDA Receptor channel (δ = 0.8). The potency of MRZ 2/579 assessed as Kd = Koff/Kon = 1.87 μM agrees well with the IC50 of 1.29 μM against steady-state currents in cultured hippocampal neurones (at −70 mV) and with the Ki in [3H]-MK-801 binding of 0.65 μM. MRZ 2/579 protected cultured cortical neurones against glutamate toxicity with an IC50 of 2.16 μM and was also effective in protecting hippocampal slices against hypoxia / hypoglycaemia-induced reduction of fEPSP amplitude in CA1 with an EC50 of 7.01 μM. MRZ 2/579 has similar potency and bio-availability to memantine in vivo assessed using microdialysis, microiontophoresis and MES-induced seizures. Initial characterization in animal models provides strong support for the assump-tion that MRZ 2/579 could be a useful therapeutic in morphine/alcohol dependence, inhibition of morphine tolerance, chronic pain and as a neuroprotective agent.
-
Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA Receptor Antagonists.
Neuropharmacology, 1998Co-Authors: P Popik, J Mamczarz, M Frączek, M Widła, M Hesselink, Wojciech DanyszAbstract:The glycine site (MRZ 2/570 and L-701,324), and uncompetitive (MRZ 2/579) NMDA Receptor Antagonists inhibited morphine-produced behaviors related to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects of glycine/NMDA Antagonists were not dose-dependent. Mice which were morphine-free for 3 days still displayed a significant severity of the withdrawal syndrome when challenged again with naloxone. This extinction of a residual morphine dependence was markedly diminished by treatment with similar doses of NMDA Receptor Antagonists at the test following the wash-out period. The rewarding impact of morphine was investigated in rats using the place preference (CPP) paradigm. All NMDA Receptor Antagonists (2.5-10 mg/kg) inhibited both the acquisition and expression of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA Receptor Antagonists given for 3 days after the end of conditioning did not influence the extinction of morphine-induced CPP. Microdialysis studies revealed that the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA Receptor antagonist. These data suggest that novel glycine site and uncompetitive NMDA Receptor Antagonists may have therapeutic potential in the treatment of opioid abuse.
Mark D Tricklebank - One of the best experts on this subject based on the ideXlab platform.
-
the mglu5 positive allosteric modulator lsn2463359 differentially modulates motor instrumental and cognitive effects of NMDA Receptor Antagonists in the rat
Neuropharmacology, 2013Co-Authors: Francois Gastambide, Gary Gilmour, Trevor W Robbins, Mark D TricklebankAbstract:Abstract Metabotropic glutamate 5 (mGlu5) Receptors are known to functionally interact with N-methyl- d -aspartate (NMDA) Receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu5 positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA Receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu5 PAM and the NMDA Receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA Receptor Antagonists PCP and MK-801, the competitive NMDA Receptor antagonist SDZ 220,581 and the GluN2B selective NMDA Receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu5 and NMDA Receptors are dependent on both the mechanism of the blockade of the Receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA Receptor Antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu5 Receptor certainly question the predictive validity of such approaches. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
-
A within-subject cognitive battery in the rat: differential effects of NMDA Receptor Antagonists
Psychopharmacology, 2010Co-Authors: Sophie Dix, Gary Gilmour, Janice W Smith, Slavinka Potts, Mark D TricklebankAbstract:The range of cognitive and psychotomimetic effects produced by Antagonists of the N-methyl-D-aspartate (NMDA) Receptor has lead to widespread usage of these molecules as pharmacological models of cognitive impairment for drug discovery. Historically, NMDA Receptor Antagonists have been used interchangeably on the assumption that they produce analogous effects. To profile a subset of these Antagonists across a novel within-subject cognitive battery in the rat. Naive male Lister Hooded rats were subjected to a series of tests in which they were required to learn a simple visuo-auditory conditional discrimination. They then underwent testing in a delayed discrimination test followed by rule reversal and rule extinction tests. All NMDA Receptor Antagonists tested impaired acquisition performance and, with the exception of ketamine and the GluN2A preferring antagonist, NVP-AAM077, impaired consolidation of extinction. GluN2B antagonism produced a singular profile with potentially enhanced delayed discrimination performance and reduced hit rates in the reversal phase. Only PCP (phencyclidine) and ketamine disrupted performance in the delay phase but did so in a delay-independent manner. MK-801, PCP and memantine all increased the hit rate in the reversal phase; whilst only MK-801 and PCP impaired extinction per se. NMDA Receptor-dependent mechanisms are requisite in the acquisition of a simple conditional discrimination and consolidation of extinction. Their role in working memory and reversal tasks appear to be less critical and potentially specific to the paradigm and NMDA Receptor antagonist used. It is clearly misleading to generalise across NMDA Antagonists with respect to their preclinical cognitive profile.
-
Diverse and often opposite behavioural effects of NMDA Receptor Antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia
Psychopharmacology, 2009Co-Authors: Gary Gilmour, Elsa Y Pioli, Janice W Smith, Michael W Conway, Wendy T Jones, Sally Loomis, Rebecca Mason, Shahram Shahabi, Mark D TricklebankAbstract:Rationale Little attention has been paid to the relative equivalence of behavioural effects of NMDA Receptor Antagonists in rodents, with different compounds often used interchangeably to “model” aspects of schizophrenia in preclinical studies. Objectives To further resolve such conjecture, the present study systematically compared eight different NMDA Receptor Antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition. Methods and results An initial locomotor activity assessment demonstrated that all Antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by ( S )-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring Antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801. Conclusion Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA Antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold.
-
diverse and often opposite behavioural effects of NMDA Receptor Antagonists in rats implications for NMDA antagonist modelling of schizophrenia
Psychopharmacology, 2009Co-Authors: Gary Gilmour, Elsa Y Pioli, Sophie Dix, Janice W Smith, Michael W Conway, Wendy T Jones, Sally Loomis, Rebecca Mason, Shahram Shahabi, Mark D TricklebankAbstract:Rationale Little attention has been paid to the relative equivalence of behavioural effects of NMDA Receptor Antagonists in rodents, with different compounds often used interchangeably to “model” aspects of schizophrenia in preclinical studies.
Wookyu Park - One of the best experts on this subject based on the ideXlab platform.
-
NMDA Receptor Antagonists enhance 5 ht2 Receptor mediated behavior head twitch response in mice
Life Sciences, 1998Co-Authors: Insook Park, Wookyu ParkAbstract:The purpose of this study was to characterize behavioral interactions between glutamatergic and serotonergic 5-HT2 Receptors. Both competitive (AP-5 [D-2-amino-5-phosphovalerate] and D-CPP [3-(2carboxypiperazine-4yl)-propylphosphonate]) and noncompetitive (MK-801 [dizocilpine], ketamine, dextrorphan and dextromethorphan) N-methyl-D-aspartate (NMDA) Receptor Antagonists markedly enhanced a selective serotonergic behavior, the head twitch response (HTR), in mice. In contrast, NMDA itself inhibited 5-hydroxytryptamine (5-HT)-induced HTR in mice. These results suggest that glutamatergic neurotransmission may modulate serotonergic function at the 5-HT2 Receptor.