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Patrick Avenet - One of the best experts on this subject based on the ideXlab platform.
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R- and L-type Ca2+ channels are insensitive to Eliprodil in rat cultured cerebellar granule neurons.
European journal of pharmacology, 1997Co-Authors: Bruno Biton, D Godet, P Granger, Patrick AvenetAbstract:We have investigated, by using the whole-cell patch-clamp technique, the Ca2+ channel antagonist properties of Eliprodil in cultured cerebellar granule cells which are known to express L-, N-, P- as well as Q- and R-type Ca2+ channels. Eliprodil maximally antagonized 50% of the voltage-dependent Ba2+ current with an IC50 of 4 microM. omega-Conotoxin-GVIA (3.2 microM) and omega-agatoxin-IVA (0.5 microM) blocked 28 and 43% of the current, respectively. When Eliprodil (30 microM) was added to omega-conotoxin-GVIA or omega-agatoxin-IVA the magnitude of the maximal inhibition was identical to that obtained with Eliprodil alone confirming a full blockade by Eliprodil of N-, P- and Q-type Ca2+ channels. The L-type channel antagonist nimodipine (10 microM) blocked 24% of the current; this blockade was fully additive to that of Eliprodil, indicating that the nimodipine-sensitive component of the current is Eliprodil-insensitive. In the presence of Eliprodil and nimodipine a residual Cd2+ sensitive current (25%), identified as the R-type current, remained unblocked. We conclude that in cerebellar granule neurons R- and L-type Ca2+ channels are insensitive to Eliprodil. The nimodipine-sensitive channels present in cerebellar granule neurons may represent a neuronal subtype of L channels distinct from that (Eliprodil-sensitive/nimodipine-sensitive) present in cortical or hippocampal neurons.
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R- and L-type Ca2+ channels are insensitive to Eliprodil in rat cultured cerebellar granule neurons.
European Journal of Pharmacology, 1997Co-Authors: Bruno Biton, D Godet, Patrick Granger, Patrick AvenetAbstract:Abstract We have investigated, by using the whole-cell patch-clamp technique, the Ca 2+ channel antagonist properties of Eliprodil in cultured cerebellar granule cells which are known to express L-, N-, P- as well as Q- and R-type Ca 2+ channels. Eliprodil maximally antagonized 50% of the voltage-dependent Ba 2+ current with an IC 50 of 4 μM. ω-Conotoxin-GVIA (3.2 μM) and ω-agatoxin-IVA (0.5 μM) blocked 28 and 43% of the current, respectively. When Eliprodil (30 μM) was added to ω-conotoxin-GVIA or ω-agatoxin-IVA the magnitude of the maximal inhibition was identical to that obtained with Eliprodil alone confirming a full blockade by Eliprodil of N-, P- and Q-type Ca 2+ channels. The L-type channel antagonist nimodipine (10 μM) blocked 24% of the current; this blockade was fully additive to that of Eliprodil, indicating that the nimodipine-sensitive component of the current is Eliprodil-insensitive. In the presence of Eliprodil and nimodipine a residual Cd 2+ sensitive current (25%), identified as the R-type current, remained unblocked. We conclude that in cerebellar granule neurons R- and L-type Ca 2+ channels are insensitive to Eliprodil. The nimodipine- sensitive channels present in cerebellar granule neurons may represent a neuronal subtype of L channels distinct from that (Eliprodil-sensitive/nimodipine-sensitive) present in cortical or hippocampal neurons.
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Antagonist properties of Eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xenopus oocytes
Neuroscience letters, 1997Co-Authors: Patrick Avenet, H. Depoortere, F. Besnard, Jacques Léonardon, David I. Graham, Bernard ScattonAbstract:We have studied the effects of a variety of N-methyl-D-aspartate (NMDA) antagonists acting at different sites of the NMDA receptor complex on NMDA-induced currents in Xenopus oocytes expressing heteromeric NR1A/NR2 and NR1A/NR2B receptors. The polyamine site antagonists Eliprodil (IC50 = 3.0 microM) and ifenprodil (IC50 = 0.27 microM) antagonized NMDA responses at NR1A/NR2B receptors but not at NR1A/NR2A receptors (IC50 > 100 microM). The channel blockers dizocilpine, memantine and phencyclidine (PCP) were equally potent antagonists at both receptor subtypes whereas dextromethorphan was four times more potent at NR1A/NR2A receptors. The glycine site antagonists L-689,560 and 7-Cl-kynurenate were 10 times more potent at NR1A/NR2A than at NR1A/NR2B receptor subtypes. The selectivity of Eliprodil and ifenprodil for the NR1A/NR2B receptor subtype may, at least partially, explain their favorable side effects profile.
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antagonist properties of Eliprodil and other nmda receptor antagonists at rat nr1a nr2a and nr1a nr2b receptors expressed in xenopus oocytes
Neuroscience Letters, 1997Co-Authors: Patrick Avenet, H. Depoortere, F. Besnard, Jacques Léonardon, David I. Graham, Bernard ScattonAbstract:We have studied the effects of a variety of N-methyl-D-aspartate (NMDA) antagonists acting at different sites of the NMDA receptor complex on NMDA-induced currents in Xenopus oocytes expressing heteromeric NR1A/NR2 and NR1A/NR2B receptors. The polyamine site antagonists Eliprodil (IC50 = 3.0 microM) and ifenprodil (IC50 = 0.27 microM) antagonized NMDA responses at NR1A/NR2B receptors but not at NR1A/NR2A receptors (IC50 > 100 microM). The channel blockers dizocilpine, memantine and phencyclidine (PCP) were equally potent antagonists at both receptor subtypes whereas dextromethorphan was four times more potent at NR1A/NR2A receptors. The glycine site antagonists L-689,560 and 7-Cl-kynurenate were 10 times more potent at NR1A/NR2A than at NR1A/NR2B receptor subtypes. The selectivity of Eliprodil and ifenprodil for the NR1A/NR2B receptor subtype may, at least partially, explain their favorable side effects profile.
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Ifenprodil and Eliprodil: Neuroprotective NMDA Receptor Antagonists and Calcium Channel Blockers
Excitatory Amino Acids, 1997Co-Authors: Chris Carter, Bruno Biton, Patrick Avenet, D. Duverger, J. Benavides, F. Besnard, A. Cudennec, J. Frost, C. Giroux, David E. GrahamAbstract:Publisher Summary This chapter discusses the role of Ifenprodil and Eliprodil as neuroprotective N-methyl- D -aspartate (NMDA) receptor antagonists and calcium channel blockers. The polyamines and ifenprodil or Eliprodil interact with their own particular binding sites and allosterically modify the actions of agonists and antagonists at the glutamate and glycine recognition sites. The polyamine-sensitive ifenprodil site is allosterically modified by figands acting at the glycine and glutamate sites of the NMDA receptor. Ifenprodil and polyamines also have opposing effects on the binding of glycine site antagonists. The modulatory effects of ifenprodil at the glycine site appear to be present at NR1 and NR1/NR2B receptor transfects, where the inhibitory effects of ifenprodil are reduced by glycine, and can also be observed at native NMDA receptors. The various glycine–polyamine interactions also predict that the inhibitory effects of glycine antagonists and ifenprodil should synergize, as demonstrated by in vivo dialysis studies. It is found that Ifenprodil and Eliprodil block the depolarizing effects or the increased entry of calcium induced by NMDA in cell culture and glutamate or NMDA-induced neurotoxicity.
Edythe D London - One of the best experts on this subject based on the ideXlab platform.
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interactions of erythro ifenprodil threo ifenprodil erythro iodoifenprodil and Eliprodil with subtypes of σ receptors
European Journal of Pharmacology, 1995Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:Observations of sigma (sigma) receptor heterogeneity have prompted interest in identifying ligands for sigma receptor subtypes. Selective ligands for the sigma-2 are unavailable, but [3H]ifenprodil labels sigma-2 sites. Therefore, isomers and analogues of ifenprodil were compared as potential sigma-2 ligands. Threo-ifenprodil and erythro-ifenprodil had high affinity (Ki congruent to 2 nM) for sigma-2 sites; erythro-iodoifenprodil had moderate affinity (Ki congruent to 46 nM); Eliprodil had lowest affinity (Ki congruent to 630 nM). Threo-ifenprodil, which has less affinity for alpha 1-adrenoceptors than erythro-ifenprodil, was slightly more selective than erythro-ifenprodil for sigma-2 sites. These results identify threo-ifenprodil as potentially useful for studies of sigma-2 receptors.
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Interactions of erythro-ifenprodil, threo-ifenprodil, erythro-iodoifenprodil, and Eliprodil with subtypes of σ receptors
European journal of pharmacology, 1995Co-Authors: Kenji Hashimoto, Edythe D LondonAbstract:Abstract Observations of sigma (σ) receptor heterogeneity have prompted interest in identifying ligands for σ receptor subtypes. Selective ligands for the σ-2 are unavailable, but [3H]ifenprodil labels σ-2 sites. Therefore, isomers and analogues of ifenprodil were compared as potential σ-2 ligands. Threo-ifenprodil and erythro-ifenprodil had high affinity ( K i ⋍ 2 nM ) for σ-2 sites; erythro-iodoifenprodil had moderate affinity ( K i ⋍ 46 nM ). Threo-ifenprodil, which has less affinity for α1-adrenoceptors than erythro-ifenprodil, was slightly more selective than erythro-ifenprodil for σ-2 sites. These results identify threo-ifenprodil as potentially useful for studies of σ-2 receptors.
Bernard Scatton - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotection afforded by a combination of Eliprodil and a thrombolytic agent, rt-PA, in a rat thromboembolic stroke model.
Brain Research, 1997Co-Authors: Delphine Lekieffre, Bernard Scatton, J. Benavides, Jean-pierre NowickiAbstract:Abstract In the present study, we have assessed the efficacy of Eliprodil, a neuroprotective agent which blocks both the modulatory polyamine site of the NMDA receptor and neuronal voltage-sensitive calcium channels, alone or in combination with the thrombolytic agent, rt-PA, in a rat embolic stroke model using a neurological score and the volume of the infarct as endpoints. Embolization was induced by intracarotid injection of an arterial blood clot. Eliprodil, administered at the dose of 1 mg/kg, iv, 10 min and 2 h 30 after embolization, reduced the neurological deficit by 54% (P
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Antagonist properties of Eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xenopus oocytes
Neuroscience letters, 1997Co-Authors: Patrick Avenet, H. Depoortere, F. Besnard, Jacques Léonardon, David I. Graham, Bernard ScattonAbstract:We have studied the effects of a variety of N-methyl-D-aspartate (NMDA) antagonists acting at different sites of the NMDA receptor complex on NMDA-induced currents in Xenopus oocytes expressing heteromeric NR1A/NR2 and NR1A/NR2B receptors. The polyamine site antagonists Eliprodil (IC50 = 3.0 microM) and ifenprodil (IC50 = 0.27 microM) antagonized NMDA responses at NR1A/NR2B receptors but not at NR1A/NR2A receptors (IC50 > 100 microM). The channel blockers dizocilpine, memantine and phencyclidine (PCP) were equally potent antagonists at both receptor subtypes whereas dextromethorphan was four times more potent at NR1A/NR2A receptors. The glycine site antagonists L-689,560 and 7-Cl-kynurenate were 10 times more potent at NR1A/NR2A than at NR1A/NR2B receptor subtypes. The selectivity of Eliprodil and ifenprodil for the NR1A/NR2B receptor subtype may, at least partially, explain their favorable side effects profile.
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antagonist properties of Eliprodil and other nmda receptor antagonists at rat nr1a nr2a and nr1a nr2b receptors expressed in xenopus oocytes
Neuroscience Letters, 1997Co-Authors: Patrick Avenet, H. Depoortere, F. Besnard, Jacques Léonardon, David I. Graham, Bernard ScattonAbstract:We have studied the effects of a variety of N-methyl-D-aspartate (NMDA) antagonists acting at different sites of the NMDA receptor complex on NMDA-induced currents in Xenopus oocytes expressing heteromeric NR1A/NR2 and NR1A/NR2B receptors. The polyamine site antagonists Eliprodil (IC50 = 3.0 microM) and ifenprodil (IC50 = 0.27 microM) antagonized NMDA responses at NR1A/NR2B receptors but not at NR1A/NR2A receptors (IC50 > 100 microM). The channel blockers dizocilpine, memantine and phencyclidine (PCP) were equally potent antagonists at both receptor subtypes whereas dextromethorphan was four times more potent at NR1A/NR2A receptors. The glycine site antagonists L-689,560 and 7-Cl-kynurenate were 10 times more potent at NR1A/NR2A than at NR1A/NR2B receptor subtypes. The selectivity of Eliprodil and ifenprodil for the NR1A/NR2B receptor subtype may, at least partially, explain their favorable side effects profile.
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Block of P-type Ca2+ channels by the NMDA receptor antagonist Eliprodil in acutely dissociated rat Purkinje cells
European journal of pharmacology, 1995Co-Authors: Bruno Biton, Patrick Granger, H. Depoortere, Bernard Scatton, Patrick AvenetAbstract:The effect of Eliprodil on P-type Ca2+ channels was investigated in acutely dissociated rat Purkinje neurons, by using the whole-cell patch-clamp technique. Eliprodil inhibited in a reversible manner the omega-agatoxin-IVA-sensitive Ba2+ current elicited by step depolarizations from a -80 mV holding voltage (IC50 = 1.9 microM). The Ba2+ current showed steady-state inactivation (V1/2 = -61 mV) which was shifted toward more positive values when the intracellular Ca2+ buffering was increased. In these conditions, the potency of Eliprodil was decreased (IC50 = 8.2 microM), suggesting a modulation by intracellular Ca2+ of the Eliprodil blockade. The potency of Eliprodil was not modified at more depolarized holding potentials and was not dependent on the frequency at which the step-depolarizations were applied (0-0.2 Hz) indicating a lack of voltage and use dependence of the Eliprodil blockade. When Eliprodil was applied in the patch-pipette at a concentration which causes full block when applied externally, the Ba2+ current amplitude was not affected and external application of Eliprodil was still efficacious, indicating an extracellular location of the binding site. Analysis of the time course of recovery from Ca2+ channel blockade obtained by concomitant application of Eliprodil with Cd2+, omega-agatoxin-IVA or fluspirilene, indicated that these later compounds did not interact with Eliprodil, suggesting that Eliprodil acts at a different site. These results demonstrate that Eliprodil blocks P-type Ca2+ channels in cerebellar Purkinje neurons and suggest that this property may contribute to its neuroprotective activity.
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Block of P-type Ca2+ channels by the NMDA receptor antagonist Eliprodil in acutely dissociated rat Purkinje cells.
European Journal of Pharmacology, 1995Co-Authors: Bruno Biton, P Granger, H. Depoortere, Bernard Scatton, Patrick AvenetAbstract:Abstract The effect of Eliprodil on P-type Ca 2+ channels was investigated in acutely dissociated rat Purkinje neurons, by using the whole-cell patch-clamp technique. Eliprodil inhibited in a reversible manner the ω-agatoxin-IVA-sensitive Ba 2+ current elicited by step depolarizations from a −80 mV holding voltage (IC 50 = 1.9 μ M). The Ba 2+ current showed steady-state inactivation ( V 1/2 = −61 mV) which was shifted toward more positive values when the intracellular Ca 2+ buffering was increased. In these conditions, the potency of Eliprodil was decreased (IC 50 = 8.2 μM), suggesting a modulation by intracellular Ca 2+ of the Eliprodil blockade. The potency of Eliprodil was not modified at more depolarized holding potentials and was not dependent on the frequency at which the step-depolarizations were applied (0–0.2 Hz) indicating a lack of voltage and use dependence of the Eliprodil blockade. When Eliprodil was applied in the patch-pipette at a concentration which causes full block when applied externally, the Ba 2+ current amplitude was not affected and external application of Eliprodil was still efficacious, indicating an extracellular location of the binding site. Analysis of the time course of recovery from Ca 2+ channel blockade obtained by concomitant application of Eliprodil with Cd 2+ , ω-agatoxin-IVA or fluspirilene, indicated that these latter compounds did not interact with Eliprodil, suggesting that Eliprodil acts at a different site. These results demonstrate that Eliprodil blocks P-type Ca 2+ channels in cerebellar Purkinje neurons and suggest that this property may contribute to its neuroprotective activity.
Bruno Biton - One of the best experts on this subject based on the ideXlab platform.
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R- and L-type Ca2+ channels are insensitive to Eliprodil in rat cultured cerebellar granule neurons.
European journal of pharmacology, 1997Co-Authors: Bruno Biton, D Godet, P Granger, Patrick AvenetAbstract:We have investigated, by using the whole-cell patch-clamp technique, the Ca2+ channel antagonist properties of Eliprodil in cultured cerebellar granule cells which are known to express L-, N-, P- as well as Q- and R-type Ca2+ channels. Eliprodil maximally antagonized 50% of the voltage-dependent Ba2+ current with an IC50 of 4 microM. omega-Conotoxin-GVIA (3.2 microM) and omega-agatoxin-IVA (0.5 microM) blocked 28 and 43% of the current, respectively. When Eliprodil (30 microM) was added to omega-conotoxin-GVIA or omega-agatoxin-IVA the magnitude of the maximal inhibition was identical to that obtained with Eliprodil alone confirming a full blockade by Eliprodil of N-, P- and Q-type Ca2+ channels. The L-type channel antagonist nimodipine (10 microM) blocked 24% of the current; this blockade was fully additive to that of Eliprodil, indicating that the nimodipine-sensitive component of the current is Eliprodil-insensitive. In the presence of Eliprodil and nimodipine a residual Cd2+ sensitive current (25%), identified as the R-type current, remained unblocked. We conclude that in cerebellar granule neurons R- and L-type Ca2+ channels are insensitive to Eliprodil. The nimodipine-sensitive channels present in cerebellar granule neurons may represent a neuronal subtype of L channels distinct from that (Eliprodil-sensitive/nimodipine-sensitive) present in cortical or hippocampal neurons.
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R- and L-type Ca2+ channels are insensitive to Eliprodil in rat cultured cerebellar granule neurons.
European Journal of Pharmacology, 1997Co-Authors: Bruno Biton, D Godet, Patrick Granger, Patrick AvenetAbstract:Abstract We have investigated, by using the whole-cell patch-clamp technique, the Ca 2+ channel antagonist properties of Eliprodil in cultured cerebellar granule cells which are known to express L-, N-, P- as well as Q- and R-type Ca 2+ channels. Eliprodil maximally antagonized 50% of the voltage-dependent Ba 2+ current with an IC 50 of 4 μM. ω-Conotoxin-GVIA (3.2 μM) and ω-agatoxin-IVA (0.5 μM) blocked 28 and 43% of the current, respectively. When Eliprodil (30 μM) was added to ω-conotoxin-GVIA or ω-agatoxin-IVA the magnitude of the maximal inhibition was identical to that obtained with Eliprodil alone confirming a full blockade by Eliprodil of N-, P- and Q-type Ca 2+ channels. The L-type channel antagonist nimodipine (10 μM) blocked 24% of the current; this blockade was fully additive to that of Eliprodil, indicating that the nimodipine-sensitive component of the current is Eliprodil-insensitive. In the presence of Eliprodil and nimodipine a residual Cd 2+ sensitive current (25%), identified as the R-type current, remained unblocked. We conclude that in cerebellar granule neurons R- and L-type Ca 2+ channels are insensitive to Eliprodil. The nimodipine- sensitive channels present in cerebellar granule neurons may represent a neuronal subtype of L channels distinct from that (Eliprodil-sensitive/nimodipine-sensitive) present in cortical or hippocampal neurons.
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Ifenprodil and Eliprodil: Neuroprotective NMDA Receptor Antagonists and Calcium Channel Blockers
Excitatory Amino Acids, 1997Co-Authors: Chris Carter, Bruno Biton, Patrick Avenet, D. Duverger, J. Benavides, F. Besnard, A. Cudennec, J. Frost, C. Giroux, David E. GrahamAbstract:Publisher Summary This chapter discusses the role of Ifenprodil and Eliprodil as neuroprotective N-methyl- D -aspartate (NMDA) receptor antagonists and calcium channel blockers. The polyamines and ifenprodil or Eliprodil interact with their own particular binding sites and allosterically modify the actions of agonists and antagonists at the glutamate and glycine recognition sites. The polyamine-sensitive ifenprodil site is allosterically modified by figands acting at the glycine and glutamate sites of the NMDA receptor. Ifenprodil and polyamines also have opposing effects on the binding of glycine site antagonists. The modulatory effects of ifenprodil at the glycine site appear to be present at NR1 and NR1/NR2B receptor transfects, where the inhibitory effects of ifenprodil are reduced by glycine, and can also be observed at native NMDA receptors. The various glycine–polyamine interactions also predict that the inhibitory effects of glycine antagonists and ifenprodil should synergize, as demonstrated by in vivo dialysis studies. It is found that Ifenprodil and Eliprodil block the depolarizing effects or the increased entry of calcium induced by NMDA in cell culture and glutamate or NMDA-induced neurotoxicity.
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Block of P-type Ca2+ channels by the NMDA receptor antagonist Eliprodil in acutely dissociated rat Purkinje cells
European journal of pharmacology, 1995Co-Authors: Bruno Biton, Patrick Granger, H. Depoortere, Bernard Scatton, Patrick AvenetAbstract:The effect of Eliprodil on P-type Ca2+ channels was investigated in acutely dissociated rat Purkinje neurons, by using the whole-cell patch-clamp technique. Eliprodil inhibited in a reversible manner the omega-agatoxin-IVA-sensitive Ba2+ current elicited by step depolarizations from a -80 mV holding voltage (IC50 = 1.9 microM). The Ba2+ current showed steady-state inactivation (V1/2 = -61 mV) which was shifted toward more positive values when the intracellular Ca2+ buffering was increased. In these conditions, the potency of Eliprodil was decreased (IC50 = 8.2 microM), suggesting a modulation by intracellular Ca2+ of the Eliprodil blockade. The potency of Eliprodil was not modified at more depolarized holding potentials and was not dependent on the frequency at which the step-depolarizations were applied (0-0.2 Hz) indicating a lack of voltage and use dependence of the Eliprodil blockade. When Eliprodil was applied in the patch-pipette at a concentration which causes full block when applied externally, the Ba2+ current amplitude was not affected and external application of Eliprodil was still efficacious, indicating an extracellular location of the binding site. Analysis of the time course of recovery from Ca2+ channel blockade obtained by concomitant application of Eliprodil with Cd2+, omega-agatoxin-IVA or fluspirilene, indicated that these later compounds did not interact with Eliprodil, suggesting that Eliprodil acts at a different site. These results demonstrate that Eliprodil blocks P-type Ca2+ channels in cerebellar Purkinje neurons and suggest that this property may contribute to its neuroprotective activity.
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Block of P-type Ca2+ channels by the NMDA receptor antagonist Eliprodil in acutely dissociated rat Purkinje cells.
European Journal of Pharmacology, 1995Co-Authors: Bruno Biton, P Granger, H. Depoortere, Bernard Scatton, Patrick AvenetAbstract:Abstract The effect of Eliprodil on P-type Ca 2+ channels was investigated in acutely dissociated rat Purkinje neurons, by using the whole-cell patch-clamp technique. Eliprodil inhibited in a reversible manner the ω-agatoxin-IVA-sensitive Ba 2+ current elicited by step depolarizations from a −80 mV holding voltage (IC 50 = 1.9 μ M). The Ba 2+ current showed steady-state inactivation ( V 1/2 = −61 mV) which was shifted toward more positive values when the intracellular Ca 2+ buffering was increased. In these conditions, the potency of Eliprodil was decreased (IC 50 = 8.2 μM), suggesting a modulation by intracellular Ca 2+ of the Eliprodil blockade. The potency of Eliprodil was not modified at more depolarized holding potentials and was not dependent on the frequency at which the step-depolarizations were applied (0–0.2 Hz) indicating a lack of voltage and use dependence of the Eliprodil blockade. When Eliprodil was applied in the patch-pipette at a concentration which causes full block when applied externally, the Ba 2+ current amplitude was not affected and external application of Eliprodil was still efficacious, indicating an extracellular location of the binding site. Analysis of the time course of recovery from Ca 2+ channel blockade obtained by concomitant application of Eliprodil with Cd 2+ , ω-agatoxin-IVA or fluspirilene, indicated that these latter compounds did not interact with Eliprodil, suggesting that Eliprodil acts at a different site. These results demonstrate that Eliprodil blocks P-type Ca 2+ channels in cerebellar Purkinje neurons and suggest that this property may contribute to its neuroprotective activity.
Robert L. Balster - One of the best experts on this subject based on the ideXlab platform.
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Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats.
European Journal of Pharmacology, 2000Co-Authors: Anton Bespalov, Edwin Zvartau, Olga A. Dravolina, Patrick M. Beardsley, Robert L. BalsterAbstract:NMDA receptor antagonists have been reported to affect learned behaviors conditioned with abused drugs, with the outcome dependent, in part, on the class of NMDA receptor antagonist used. The present study tested the ability of various site-selective NMDA receptor antagonists to modify cocaine-conditioned motor activity. Two procedures were used for independently assessing drug effects on spontaneous activity and expression of cocaine-conditioned behavior. In the conditioning experiments, rats were administered i.p. injections of cocaine (30 mg/kg) or saline paired with distinctive environments. Spontaneous horizontal activity was dose-dependently enhanced by dizocilpine (0.03-0.3 mg/kg) and memantine (1-30 mg/kg), but not by D-CPPene (3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494; 1-10 mg/kg), ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2, 3-quinoxalinedione; 3-56 mg/kg), or Eliprodil (3-30 mg/kg). Higher doses of memantine, D-CPPene (1-10 mg/kg), Eliprodil (3-30 mg/kg), or ACEA-1021 reduced vertical activity. Following five cocaine-environment pairings, rats displayed significant increases in motor activity when exposed to the cocaine-paired environment. The following antagonists were administered prior to the conditioning test: dizocilpine (MK-801; 0.03-0.1 mg/kg), memantine (1-10 mg/kg), D-CPPene (0.3-3 mg/kg), ACEA-1021 (3-10 mg/kg), and Eliprodil (1-10 mg/kg). Of these, memantine, ACEA-1021 and, to the lesser degree, Eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity. These results show that cocaine-conditioned behaviors can be selectively modulated by some, but not all, NMDA receptor antagonists.
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N-Methyl-D-aspartate receptor antagonists and the development of tolerance to the discriminative stimulus effects of morphine in rats.
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Anton Bespalov, Robert L. Balster, Patrick M. BeardsleyAbstract:Several reports have indicated that N -methyl-d-aspartate (NMDA) receptor antagonists prevent the development of analgesic tolerance to opiates. Some effects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water (vehicle) using a standard, two-lever fixed ratio 10 schedule of food reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days b.i.d.) was administered, which induced tolerance-like rightward shifts in the dose-effect curves for both morphine’s discriminative stimulus and response rate-suppressing effects. Withdrawal-induced, response rate reductions indicative of behavioral dependence appeared as well. Separate groups were then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizocilpine (0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (d-CPPene; 3 and 5.6 mg/kg i.p.), Eliprodil (17.3 mg/kg i.p.), or R (+)-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The development of tolerance to morphine’s stimulus effects was attenuated by Eliprodil and the higher dose of d-CPPene, but not by dizocilpine, the lower dose ofd-CPPene, nor R (+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists prevented the induction of tolerance to morphine’s response rate effects. Dizocilpine and d-CPPene (5.6 mg/kg) appeared to prevent the induction of behavioral dependence as well. NMDA antagonists can prevent tolerance to the discriminative stimulus effects of morphine, and perhaps to its behavioral dependence effects, but their site of action on the NMDA receptor complex confers a different ability to do so.
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Interactions Between N-Methyl-d-Aspartate Receptor Antagonists and the Discriminative Stimulus Effects of Morphine in Rats
Pharmacology biochemistry and behavior, 1998Co-Authors: Anton Bespalov, Patrick M. Beardsley, Robert L. BalsterAbstract:Abstract NMDA receptor antagonists have previously been reported to alter some pharmacological and behavioral effects of acute and chronic opioid administration. The present study assessed the interactions of NMDA antagonists with the discriminative stimulus properties of morphine. Adult male Long–Evans rats were trained to discriminate 3.2 mg/kg of SC morphine from water under a two-lever fixed-ratio 10 schedule of food reinforcement. During test sessions, IP injections of the noncompetitive NMDA receptor antagonist dizocilpine (0.03–0.2 mg/kg), the competitive antagonists NPC 17742 (1–16 mg/kg), and SDZ 220-581 (0.1–3 mg/kg), the polyamine site antagonist Eliprodil (3–17.3 mg/kg), the glycine-site partial agonist (+)-HA-966 (3–56 mg/kg), and the nonselective glutamate antagonist kynurenic acid (30–150 mg/kg) were coadministered with SC morphine (1–3.2 mg/kg; interaction tests) or water (generalization tests). In generalization tests, none of the compounds completely substituted for morphine. Concurrent administration of morphine and NMDA antagonists did not greatly alter the discriminative stimulus properties of morphine. Various doses of NPC 17742, SDZ 220-581, or (+)-HA-966 somewhat increased levels of morphine-appropriate lever selection, whereas some attenuation of morphine-lever selection was obtained when morphine was coadministered with Eliprodil. These results show that NMDA antagonists have minimal interactions with the discriminative stimulus effects of morphine.
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Effects of modulation of NMDA neurotransmission on response rate and duration in a conflict procedure in rats.
Neuropharmacology, 1998Co-Authors: Jenny L. Wiley, Amelia D. Compton, Jennifer D Holcomb, Sarah E Mccallum, Steven A Varvel, Joseph H. Porter, Robert L. BalsterAbstract:N-Methyl-D-aspartate (NMDA) antagonists and gamma-aminobutyric acid agonists share a number of common pharmacological properties, including motor and anticonvulsant effects. In the present study, site-selective NMDA antagonists were evaluated for potential anxiolytic efficacy and motor impairment in a modified Geller-Seifter conflict procedure, an animal model widely used to screen drugs for anxiolytic effects. Male Sprague-Dawley rats were trained to respond for food reward under a multiple FI 30 s (food only), FR 10 (food + shock) operant schedule. Consistent with the results of previous studies, the benzodiazepines chlordiazepoxide and diazepam selectively increased punished responding and increased response durations at higher doses. The competitive NMDA antagonist CGP 37,849 increased punished responding at some doses, though not selectively, and also increased response duration in both schedule components. The glycine-site modulators milacemide, ACEA 1011 and ACEA 1021, the NR2B-selective polyamine site antagonist Eliprodil and NMDA did not produce anticonflict effects at any dose and had inconsistent effects on response durations. These results suggest that the anticonflict effects of NMDA antagonists are not as reliable as those of the benzodiazepines. Further research is needed to clarify the experimental conditions under which the anxiolytic potential of NMDA antagonists is most evident.
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Discriminative stimulus effects of site-selective N-methyl-d-aspartate antagonists in NPC 17742-trained rats and squirrel monkeys
Psychopharmacology, 1997Co-Authors: J. L. Wiley, Robert L. BalsterAbstract:Drug discrimination studies in rats and monkeys with competitive N -methyl- d -aspartate (NMDA) antagonists as training drugs have shown that these drugs typically cross-substitute for each other, whereas phencyclidine (PCP)-like NMDA channel blockers produce partial, if any, substitution. In the present study, rats and squirrel monkeys were trained to discriminate the competitive NMDA antagonist, NPC 17742, from vehicle in a two-lever drug discrimination procedure for food reinforcement. The competitive NMDA antagonists, NPC 12626, SDZ EAA 494 ( d -CPPene), and MDL 100,453 fully substituted for NPC 17742 in monkeys or in rats. The relative potencies of these compounds were similar across species. Open channel blockers, PCP and dizocilpine, and the tricyclic antidepressant and low affinity PCP-site ligand, desipramine, produced minimal responding on the NPC 17742-associated lever in rats or monkeys. The glycine-site modulators, (+)-HA-966, ACEA 1021 and milacemide, and the polyamine/NR2B-selective antagonist, Eliprodil, also failed to substitute fully for NPC 17742 in rats and monkeys. These data complement and extend results of previous studies which have shown a lack of PCP-like discriminative stimulus effects of these non-competitive NMDA antagonists by further showing that they also do not share discriminative stimulus effects with those produced by many competitive NMDA antagonists. These observations would support a prediction that differences in side-effect profiles should emerge among types of NMDA antagonists.