The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Phil Skolnick - One of the best experts on this subject based on the ideXlab platform.
-
1-Aminocyclopropanecarboxylic Acid (ACPC) produces procognitive but not antipsychotic-like effects in rats
Psychopharmacology, 2015Co-Authors: Piotr Popik, Ramon Trullas, Malgorzata Holuj, Agnieszka Nikiforuk, Tomasz Kos, Phil SkolnickAbstract:Rationale In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-Aminocyclopropanecarboxylic Acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors. Objectives We investigated the procognitive and antipsychotic-like effects of ACPC in rats treated with phencyclidine (PCP) or ketamine (KET), compounds that produce psychotic-like symptoms in humans and laboratory animals. Methods Cognitive effects were investigated in the novel object recognition (NOR) and attentional set-shifting tests (ASST). In addition, the effects of ACPC were investigated in PCP-induced hyperactivity, conditioned avoidance response (CAR), and prepulse inhibition (PPI) tests. The effects on attention and impulsivity were measured in the five-choice serial reaction time task (5-CSRTT). Results ACPC (200–400 mg/kg) inhibited memory fading in naive rats and like clozapine prevented PCP- and KET-induced amnesia in the NOR. In naive animals, ACPC at 400 but not 200 mg/kg enhanced cognitive flexibility in the ASST, as the animals required fewer trials to reach the criteria during the extra-dimensional phase. In contrast, ACPC did not affect PCP-induced hyperactivity, CAR, and PPI as well as attention and impulsivity in the 5-CSRTT. Conclusion The present study demonstrates that ACPC enhanced both object recognition memory and cognitive flexibility dependent on the prefrontal cortex, but did not affect impulsivity nor exhibit an antipsychotic-like profile.
-
1 Aminocyclopropanecarboxylic Acid acpc produces procognitive but not antipsychotic like effects in rats
Psychopharmacology, 2015Co-Authors: Piotr Popik, Ramon Trullas, Malgorzata Holuj, Agnieszka Nikiforuk, Tomasz Kos, Phil SkolnickAbstract:Rationale In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-Aminocyclopropanecarboxylic Acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors.
-
putative partial agonist 1 Aminocyclopropanecarboxylic Acid acts concurrently as a glycine site agonist and a glutamate site antagonist at n methyl d aspartate receptors
Molecular Pharmacology, 1999Co-Authors: Rinat Nahumlevy, Phil Skolnick, Linda H Fossom, Morris BenvenisteAbstract:1-Aminocyclopropanecarboxylic Acid (ACPC) has been shown to protect against neuronal cell death after ischemic insult in vivo. Such results can be correlated with in vitro assays in which ACPC protected neurons against glutamate-induced neurotoxicity by reducing the activity of N -methyl-d-aspartate (NMDA) channel activation. Electrophysiological studies have determined that ACPC inhibits NMDA receptor activity by acting as a glycine-binding site partial agonist. In this study, rapid drug perfusion combined with whole-cell voltage-clamp was used to elicit and measure the effects of ACPC on NMDA receptor-mediated responses from cultured hippocampal neurons and cerebellar granule cells. The ACPC steady-state dose-response curve had both stimulatory and inhibitory phases. Half-maximal activation by ACPC as a glycine-site agonist was 0.7 to 0.9 μM. Half-maximal inhibition by ACPC was dependent on NMDA concentration. Peak responses to a >100 μM ACPC pulse in the presence of 1 μM glutamate were similar to those of glycine but decayed to a steady-state amplitude below that of glycine. The removal of ACPC initially caused an increase in inward current followed by a subsequent decrease to baseline levels. This suggests that relief of low-affinity antagonism occurs before high-affinity agonist dissociation. Simulations of ACPC action by a two glutamate-binding site/two glycine-binding site model for NMDA channel activation in conjunction with the concurrent role of ACPC as a glycine-site full agonist and glutamate-site competitive antagonist were able to successfully approximate experimental results.
-
3h 1 Aminocyclopropanecarboxylic Acid a novel probe for strychnine insensitive glycine receptors
European Journal of Pharmacology, 1995Co-Authors: Piotr Popik, Gabriel Nowak, Anita H Lewin, Richard T Layer, Berthold Berrang, Phil SkolnickAbstract:Abstract [3H]1-Aminocyclopropanecarboxylic Acid (ACPC) exhibits high affinity, specific binding to strychnine-insensitive glycine receptors. In extensively washed rat forebrain membranes, the specific binding of [3H]ACPC was optimal at 25°C in the presence of 10 mM MgCl2. Comparable levels of specific [3H]ACPC binding were obtained using centrifugation and filtration for separation of bound from free radioligand. [3H]ACPC labels two sites with Kd1 and Bmax1 values of 129±34 nM and 2.30±0.37 pmol/mg protein and Kd2 and Bmax2 values of 7.26±1.69 μM and 20.6±2.2 pmol/mg protein for the high and low affinity sites, respectively. The Kd of [3H]ACPC (66 nM) estimated under non-equilibrium conditions (koff=8.91±0.78×10−3 s−1; kon=1.35×10−4 nM−1 s−1) was similar to the value obtained for the high affinity site obtained by equilibrium binding. The Kd1 of [3H]ACPC is in good agreement with the previously reported Ki values of ACPC to inhibit the binding of other glycinergic ligands including [3H]glycine, [3H]5,7-dichlorokynurenic Acid (5,7-DCKA) and [3H]L-689,560 ((±)-4-(trans)-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline). Moreover, the potencies of a series of glycine site ligands, including glycine, ACPC, 1-aminocyclobutanecarboxylic Acid (ACBC), 5,7-DCKA, 7-chlorokynurenic Acid (7-CKA), R(+)-3-amino-1-hydroxy-2-pyrrolidine (HA-966) and D -serine, to inhibit [3H]ACPC binding were highly correlated with their potencies to inhibit [3H]glycine and [3H]5,7-DCKA binding (r2=0.98−0.51). These results demonstrate that [3H]ACPC is a useful tool for examining the neurochemical and pharmacological properties of strychnine-insensitive glycine receptors.
-
neuroprotective actions of 1 Aminocyclopropanecarboxylic Acid acpc a partial agonist at strychnine insensitive glycine sites
Neurological Research, 1995Co-Authors: Linda H Fossom, Dag K J E Von Lubitz, Rick C S Lin, Phil SkolnickAbstract:Abstract1-Aminocyclopropanecarboxylic Acid is a high affinity ligand with partial agonist properties at strychnine-insensitive glycine sites associated with the N-methyl-D-aspartate subtype of glutamate receptors. Since occupation of these sites appears required for operation of N-methyl-D-aspartate receptor coupled cation channels, it was hypothesized that a glycine partial agonist could function as an N-methyl-D-aspartate antagonist. This hypothesis was examined by evaluating the in vivo and in vitro neuroprotective actions of 1-Aminocyclopropanecarboxylic Acid. 1-Aminocyclopropanecarboxlic Acid (150-600 mg kg~1) administered to gerbils five minutes following twenty minutes of forebrain ischemia significantly improved seven day survival; the optimal dose (300 mg kg~1) increased 7 day survival >4-fold, from 20% to 92%. Survival of hippocampal CA1 neurons (quantitated 7 days post-ischemia) was significantly (~ 3-fold) increased by the 600 mg kg~1 dose. Seven day survival was not significantly increased wh...
Ramon Trullas - One of the best experts on this subject based on the ideXlab platform.
-
1 Aminocyclopropanecarboxylic Acid acpc produces procognitive but not antipsychotic like effects in rats
Psychopharmacology, 2015Co-Authors: Piotr Popik, Ramon Trullas, Malgorzata Holuj, Agnieszka Nikiforuk, Tomasz Kos, Phil SkolnickAbstract:Rationale In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-Aminocyclopropanecarboxylic Acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors.
-
1-Aminocyclopropanecarboxylic Acid (ACPC) produces procognitive but not antipsychotic-like effects in rats
Psychopharmacology, 2015Co-Authors: Piotr Popik, Ramon Trullas, Malgorzata Holuj, Agnieszka Nikiforuk, Tomasz Kos, Phil SkolnickAbstract:Rationale In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-Aminocyclopropanecarboxylic Acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors. Objectives We investigated the procognitive and antipsychotic-like effects of ACPC in rats treated with phencyclidine (PCP) or ketamine (KET), compounds that produce psychotic-like symptoms in humans and laboratory animals. Methods Cognitive effects were investigated in the novel object recognition (NOR) and attentional set-shifting tests (ASST). In addition, the effects of ACPC were investigated in PCP-induced hyperactivity, conditioned avoidance response (CAR), and prepulse inhibition (PPI) tests. The effects on attention and impulsivity were measured in the five-choice serial reaction time task (5-CSRTT). Results ACPC (200–400 mg/kg) inhibited memory fading in naive rats and like clozapine prevented PCP- and KET-induced amnesia in the NOR. In naive animals, ACPC at 400 but not 200 mg/kg enhanced cognitive flexibility in the ASST, as the animals required fewer trials to reach the criteria during the extra-dimensional phase. In contrast, ACPC did not affect PCP-induced hyperactivity, CAR, and PPI as well as attention and impulsivity in the 5-CSRTT. Conclusion The present study demonstrates that ACPC enhanced both object recognition memory and cognitive flexibility dependent on the prefrontal cortex, but did not affect impulsivity nor exhibit an antipsychotic-like profile.
-
effect of 1 Aminocyclopropanecarboxylic Acid on n methyl d aspartate stimulated 3h noradrenaline release in rat hippocampal synaptosomes
British Journal of Pharmacology, 1996Co-Authors: M V Clos, Ramon Trullas, Garcia A Sanz, Albert BadiaAbstract:1. The effect of 1-Aminocyclopropanecarboxylic Acid (ACPC), a partial agonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex that exhibits neuroprotective, anxiolytic and antidepressant-like actions, was investigated in a functional assay for presynaptic NMDA receptors. 2. NMDA (100 microM) produced a 36% increase of tritium efflux above basal efflux in rat hippocampal synaptosomes preincubated with [3H]-noradrenaline ([3H]-NA), reflecting a release of tritiated noradrenaline. This effect was prevented by 10 microM 7-chlorokynurenic Acid, an antagonist of the glycine site of the NMDA receptor. 3. Glycine enhanced the effect of NMDA with Emax and EC50 values of 84 +/- 11% and 1.82 +/- 0.04 microM, respectively. ACPC potentiated the effect of NMDA on tritium overflow with a lower EC50 (43 +/- 6 nM) and a lower maximal effect (Emax = 40 +/- 9%) than glycine. Furthermore, ACPC (0.1 microM) shifted the EC50 of glycine from 1.82 microM to > or = 3 mM. 4. These results show that ACPC can reduce the potentiation by glycine of NMDA-evoked [3H]-NA release and hence, may act as an antagonist at the glycine site of presynaptic hippocampal NMDA receptors when the concentration of glycine is high.
-
adaptive changes in the n methyl d aspartate receptor complex after chronic treatment with imipramine and 1 Aminocyclopropanecarboxylic Acid
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: Gabriel Nowak, Ramon Trullas, Richard T Layer, P Skolnick, Ian A. PaulAbstract:Chronic (14 daily injections) treatment of mice with the prototypic tricyclic antidepressant imipramine significantly alters ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. These effects were compared to a chronic regimen of 1-Aminocyclopropanecarboxylic Acid, a high-affinity partial agonist at strychnine-insensitive glycine receptors which mimics the effects of imipramine in preclinical models predictive of antidepressant action. Changes in the NMDA receptor complex after chronic, but not acute treatment with imipramine were manifested as: 1) a reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic Acid binding to strychnine-insensitive glycine receptors; 2) a decrease in the proportion of high-affinity glycine sites inhibiting [3H]CGP 39653 binding to NMDA receptors; and 3) a decrease in basal [3H]MK-801 binding (under nonequilibrium conditions) to sites within NMDA receptor-coupled cation channels which was reversible by the addition of glutamate. These effects were observed in cerebral cortex, but not in hippocampus, striatum or basal forebrain. Chronic treatment with 1-Aminocyclopropanecarboxylic Acid resulted in changes which paralleled those of imipramine on ligand binding to the NMDA receptor complex, but the reduction in basal [3H]MK-801 binding did not achieve statistical significance. These findings indicate that adaptive changes in the NMDA receptor complex could be a feature common to chronic treatment with structurally unrelated antidepressants.
-
Chronic treatment with 1-Aminocyclopropanecarboxylic Acid desensitizes behavioral responses to compounds acting at the N-methyl-d-aspartate receptor complex
Psychopharmacology, 1992Co-Authors: Phil Skolnick, Rachel Miller, Andrew Young, Kathleen Boje, Ramon TrullasAbstract:Functional antagonists at the N-methyl- d -aspartate (NMDA) receptor complex produce anti-depressant-like actions in preclinical models. Thus, an injection of a glycine partial agonist (1-Aminocyclopropanecarboxylic Acid; ACPC), a competitive NMDA antagonist (2-amino-7-phosphonoheptanoic Acid; AP-7) or a use-dependent cation channel blocker (MK-801) reduced immobility in the forced swim test (FST) with efficacies comparable to imipramine (Trullas and Skolnick 1990). Seven daily injections of ACPC (200–400 mg/kg) abolished the effects of both this compound (200–1200 mg/kg) and AP-7 (200–300 mg/kg) in the FST. The loss in effectiveness of ACPC required 7 days of treatment to become fully manifest, and was reversed by discontinuing treatment. Other agents active in the FST (e.g. MK-801, imipramine, and nifedipine) were unaffected by this regimen. Moreover, ACPC and AP-7 remained active in the FST following repeated injections of MK-801, AP-7, or imipramine. Chronic treatment with ACPC did not affect its actions in the elevated plus-maze, but significantly attenuated the convulsant and lethal effects of NMDA (125 mg/kg). Tissue levels of ACPC indicate the modified behavioral responses produced by chronic treatment are not attributable to pharmacokinetic factors. These findings suggest repeated administration of ACPC may effect an “uncoupling” of NMDA and glycine receptors, resulting in an apparent desensitization of the behavioral actions of substances acting at these sites.
Piotr Popik - One of the best experts on this subject based on the ideXlab platform.
-
1 Aminocyclopropanecarboxylic Acid acpc produces procognitive but not antipsychotic like effects in rats
Psychopharmacology, 2015Co-Authors: Piotr Popik, Ramon Trullas, Malgorzata Holuj, Agnieszka Nikiforuk, Tomasz Kos, Phil SkolnickAbstract:Rationale In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-Aminocyclopropanecarboxylic Acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors.
-
1-Aminocyclopropanecarboxylic Acid (ACPC) produces procognitive but not antipsychotic-like effects in rats
Psychopharmacology, 2015Co-Authors: Piotr Popik, Ramon Trullas, Malgorzata Holuj, Agnieszka Nikiforuk, Tomasz Kos, Phil SkolnickAbstract:Rationale In addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-Aminocyclopropanecarboxylic Acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors. Objectives We investigated the procognitive and antipsychotic-like effects of ACPC in rats treated with phencyclidine (PCP) or ketamine (KET), compounds that produce psychotic-like symptoms in humans and laboratory animals. Methods Cognitive effects were investigated in the novel object recognition (NOR) and attentional set-shifting tests (ASST). In addition, the effects of ACPC were investigated in PCP-induced hyperactivity, conditioned avoidance response (CAR), and prepulse inhibition (PPI) tests. The effects on attention and impulsivity were measured in the five-choice serial reaction time task (5-CSRTT). Results ACPC (200–400 mg/kg) inhibited memory fading in naive rats and like clozapine prevented PCP- and KET-induced amnesia in the NOR. In naive animals, ACPC at 400 but not 200 mg/kg enhanced cognitive flexibility in the ASST, as the animals required fewer trials to reach the criteria during the extra-dimensional phase. In contrast, ACPC did not affect PCP-induced hyperactivity, CAR, and PPI as well as attention and impulsivity in the 5-CSRTT. Conclusion The present study demonstrates that ACPC enhanced both object recognition memory and cognitive flexibility dependent on the prefrontal cortex, but did not affect impulsivity nor exhibit an antipsychotic-like profile.
-
3h 1 Aminocyclopropanecarboxylic Acid a novel probe for strychnine insensitive glycine receptors
European Journal of Pharmacology, 1995Co-Authors: Piotr Popik, Gabriel Nowak, Anita H Lewin, Richard T Layer, Berthold Berrang, Phil SkolnickAbstract:Abstract [3H]1-Aminocyclopropanecarboxylic Acid (ACPC) exhibits high affinity, specific binding to strychnine-insensitive glycine receptors. In extensively washed rat forebrain membranes, the specific binding of [3H]ACPC was optimal at 25°C in the presence of 10 mM MgCl2. Comparable levels of specific [3H]ACPC binding were obtained using centrifugation and filtration for separation of bound from free radioligand. [3H]ACPC labels two sites with Kd1 and Bmax1 values of 129±34 nM and 2.30±0.37 pmol/mg protein and Kd2 and Bmax2 values of 7.26±1.69 μM and 20.6±2.2 pmol/mg protein for the high and low affinity sites, respectively. The Kd of [3H]ACPC (66 nM) estimated under non-equilibrium conditions (koff=8.91±0.78×10−3 s−1; kon=1.35×10−4 nM−1 s−1) was similar to the value obtained for the high affinity site obtained by equilibrium binding. The Kd1 of [3H]ACPC is in good agreement with the previously reported Ki values of ACPC to inhibit the binding of other glycinergic ligands including [3H]glycine, [3H]5,7-dichlorokynurenic Acid (5,7-DCKA) and [3H]L-689,560 ((±)-4-(trans)-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline). Moreover, the potencies of a series of glycine site ligands, including glycine, ACPC, 1-aminocyclobutanecarboxylic Acid (ACBC), 5,7-DCKA, 7-chlorokynurenic Acid (7-CKA), R(+)-3-amino-1-hydroxy-2-pyrrolidine (HA-966) and D -serine, to inhibit [3H]ACPC binding were highly correlated with their potencies to inhibit [3H]glycine and [3H]5,7-DCKA binding (r2=0.98−0.51). These results demonstrate that [3H]ACPC is a useful tool for examining the neurochemical and pharmacological properties of strychnine-insensitive glycine receptors.
-
one step preparation of 2 3 3h 1 Aminocyclopropanecarboxylic Acid a useful ligand for strychnine insensitive glycine receptors
Journal of Labelled Compounds and Radiopharmaceuticals, 1994Co-Authors: Anita H Lewin, Piotr Popik, Pamela B Lamb, Phil SkolnickAbstract:Catalytic hydrogenation of 1-aminocyclopropenecarboxylic Acid under tritium gas afforded [2,3-3H]1-Aminocyclopropanecarboxylic Acid with specific activity 26 Ci/mmol, determined by a combination of 1H and 3H NMR. Pilot radioligand binding assays indicate this compound will be a useful probe for the NMDA receptor-associated strychnine-insensitive glycine receptor.
Gabriel Nowak - One of the best experts on this subject based on the ideXlab platform.
-
Chronic glycine treatment desensitizes the behavioral response to 1-Aminocyclopropanecarboxylic Acid (ACPC), a partial agonist at the strychnine-insensitive glycine site of the NMDA receptor complex.
Journal of neural transmission (Vienna Austria : 1996), 2000Co-Authors: Gabriel Nowak, Y Li, Ian A. PaulAbstract:Chronic treatment with 1-Aminocyclopropanecarboxylic Acid (ACPC) but not with dizocilpine or imipramine produces desensitization to the behavioral response in ACPC challenge in the forced swim test (forced swim test). The mechanism by which ACPC produces this effect is unclear and may depend upon either its functional antagonist or its agonist properties at the NMDA receptor. We now report that chronic treatment with glycine or ACPC desensitizes the behavioral effect of challenge with ACPC in the forced swim test. The desensitization of the acute effects of ACPC cannot be explained by the presence of residual glycine because 24 h after the last of 14 daily glycine injections (i.e. the time of forced swim test) cortical and hippocampal glycine concentrations were unchanged. Likewise, the affinity of glycine to displace specific [3H]5,7-DCKA binding to glycine sites of the NMDA receptor complex was unchanged by chronic glycine administration. These results support the hypothesis that antidepressants produce adaptation of the NMDA receptor complex by mechanisms other than simply increasing synaptic glycine concentrations. Moreover, these results indicate that the behavioral adaptation in the forced swim test induced by chronic treatment with ACPC results from its agonist properties.
-
3h 1 Aminocyclopropanecarboxylic Acid a novel probe for strychnine insensitive glycine receptors
European Journal of Pharmacology, 1995Co-Authors: Piotr Popik, Gabriel Nowak, Anita H Lewin, Richard T Layer, Berthold Berrang, Phil SkolnickAbstract:Abstract [3H]1-Aminocyclopropanecarboxylic Acid (ACPC) exhibits high affinity, specific binding to strychnine-insensitive glycine receptors. In extensively washed rat forebrain membranes, the specific binding of [3H]ACPC was optimal at 25°C in the presence of 10 mM MgCl2. Comparable levels of specific [3H]ACPC binding were obtained using centrifugation and filtration for separation of bound from free radioligand. [3H]ACPC labels two sites with Kd1 and Bmax1 values of 129±34 nM and 2.30±0.37 pmol/mg protein and Kd2 and Bmax2 values of 7.26±1.69 μM and 20.6±2.2 pmol/mg protein for the high and low affinity sites, respectively. The Kd of [3H]ACPC (66 nM) estimated under non-equilibrium conditions (koff=8.91±0.78×10−3 s−1; kon=1.35×10−4 nM−1 s−1) was similar to the value obtained for the high affinity site obtained by equilibrium binding. The Kd1 of [3H]ACPC is in good agreement with the previously reported Ki values of ACPC to inhibit the binding of other glycinergic ligands including [3H]glycine, [3H]5,7-dichlorokynurenic Acid (5,7-DCKA) and [3H]L-689,560 ((±)-4-(trans)-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline). Moreover, the potencies of a series of glycine site ligands, including glycine, ACPC, 1-aminocyclobutanecarboxylic Acid (ACBC), 5,7-DCKA, 7-chlorokynurenic Acid (7-CKA), R(+)-3-amino-1-hydroxy-2-pyrrolidine (HA-966) and D -serine, to inhibit [3H]ACPC binding were highly correlated with their potencies to inhibit [3H]glycine and [3H]5,7-DCKA binding (r2=0.98−0.51). These results demonstrate that [3H]ACPC is a useful tool for examining the neurochemical and pharmacological properties of strychnine-insensitive glycine receptors.
-
adaptive changes in the n methyl d aspartate receptor complex after chronic treatment with imipramine and 1 Aminocyclopropanecarboxylic Acid
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: Gabriel Nowak, Ramon Trullas, Richard T Layer, P Skolnick, Ian A. PaulAbstract:Chronic (14 daily injections) treatment of mice with the prototypic tricyclic antidepressant imipramine significantly alters ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. These effects were compared to a chronic regimen of 1-Aminocyclopropanecarboxylic Acid, a high-affinity partial agonist at strychnine-insensitive glycine receptors which mimics the effects of imipramine in preclinical models predictive of antidepressant action. Changes in the NMDA receptor complex after chronic, but not acute treatment with imipramine were manifested as: 1) a reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic Acid binding to strychnine-insensitive glycine receptors; 2) a decrease in the proportion of high-affinity glycine sites inhibiting [3H]CGP 39653 binding to NMDA receptors; and 3) a decrease in basal [3H]MK-801 binding (under nonequilibrium conditions) to sites within NMDA receptor-coupled cation channels which was reversible by the addition of glutamate. These effects were observed in cerebral cortex, but not in hippocampus, striatum or basal forebrain. Chronic treatment with 1-Aminocyclopropanecarboxylic Acid resulted in changes which paralleled those of imipramine on ligand binding to the NMDA receptor complex, but the reduction in basal [3H]MK-801 binding did not achieve statistical significance. These findings indicate that adaptive changes in the NMDA receptor complex could be a feature common to chronic treatment with structurally unrelated antidepressants.
Joseph B Long - One of the best experts on this subject based on the ideXlab platform.
-
prolonged pre exposure to 1 Aminocyclopropanecarboxylic Acid protects against subsequent glutamate toxicity in vitro
European Journal of Pharmacology, 1997Co-Authors: Yu Lin, Joseph B LongAbstract:Abstract Sustained 20 h pre-exposure to 1 mM 1-Aminocyclopropanecarboxylic Acid (ACPC, which was removed 30 min before addition of 25 μM glutamate) significantly reduced the subsequent neurotoxicity of glutamate in cultured forebrain and cerebellar neurons. The magnitude of neuronal protection was further enhanced if the neurons pretreated with ACPC were re-exposed to ACPC during glutamate challenge. These results closely resemble earlier findings with cultured spinal cord neurons and indicate that these primary cell culture preparations might be suitable for the assessment of the mechanism(s) underlying chronic ACPC-induced modification of the NMDA receptor complex.
-
acute or prolonged exposure to 1 Aminocyclopropanecarboxylic Acid protects spinal neurons against nmda toxicity
European Journal of Pharmacology, 1996Co-Authors: Yu Lin, Joseph B LongAbstract:1-Aminocyclopropanecarboxylic Acid (ACPC) is a high affinity partial agonist for the glycine binding site within the NMDA receptor complex. Chronic treatment with ACPC in vivo appears to reversibly desensitize the NMDA receptor complex, prompting suggestions that it might provide an effective means of ameliorating degenerative mechanisms mediated through this ligand-gated ion channel. In the present experiments, cultured rat spinal cord neurons were used to further examine the effects of acute and sustained ACPC exposures on N-methyl-d-aspartate (NMDA)-induced neurotoxicity. Cell damage was quantitatively assessed using a tetrazolium salt colorimetric assay. With coincubation, 1 mM ACPC significantly reduced the neuronal cell damage caused by 30 min exposure to 25 or 50 μM concentrations of NMDA, but, in contrast to other competitive and non-competitive NMDA receptor antagonists (d-(-)-2-amino-5-phosphonovaleric Acid (APV), dizocilpine maleate (MK-801) and 7-chlorokynurenic Acid (7-CK)), it failed to alter the cell injury induced by 100 μM NMDA. The protective effect of ACPC was competitively abolished by coaddition of glycine, verifying that it was mediated through glycine binding sites. Sustained 20 h exposure to 1 mM ACPC (which was removed 30 min before addition of 25 μM NMDA) also caused cells to be significantly less responsive to the neurotoxic effects of NMDA. Pre-exposure to ACPC for shorter intervals (< 1 h) failed to alter subsequent NMDA toxicity. Acute or sustained exposures to ACPC alone did not affect cell viability. These results support earlier indications that: (1) ACPC provides an effective means of antagonizing excitotoxic phenomena, and (2) sustained exposure to ACPC desensitizes the NMDA receptor complex.
-
1 Aminocyclopropanecarboxylic Acid protects against dynorphin a induced spinal injury
European Journal of Pharmacology, 1994Co-Authors: Joseph B Long, Phil SkolnickAbstract:Lumbar subarachnoid injection of dynorphin A causes an ischemia-induced neuronal degeneration and persistent hindlimb paralysis. The protective effects of a variety of competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists indicate that activation of the NMDA receptor complex is essential for dynorphin A-induced spinal cord injury. 1-Aminocyclopropanecarboxylic Acid (ACPC) is a high affinity, partial agonist at strychnine-insensitive glycine receptors associated with the NMDA receptor complex. Pretreatment of rats with ACPC (100 and 200 mg/kg, i.p., 30 min prior to dynorphin A) significantly eliminated the persistent hindlimb motor deficits and neuropathological changes produced by 20 nmol of this peptide. The neuroprotective effects of ACPC (100 mg/kg, i.p.) were abolished by parenteral administration of glycine (800 mg/kg, 30 min prior to ACPC), consistent with other in vivo and in vitro studies indicating that the pharmacological actions of ACPC are effected through strychnine-insensitive glycine receptors. When given instead as six daily injections (200 mg/kg, i.p.) followed by an injection-free day, ACPC also significantly improved neurological recovery following dynorphin-A injection. These results support earlier indications that: (1) activation of the NMDA receptor complex plays a critical role in mediating dynorphin A-induced rat spinal cord injury; (2) ACPC provides an effective means of antagonizing excitotoxic phenomena; and (3) chronic administration of ACPC can elicit a persistent change in the NMDA receptor complex.
