strychnine and 1-aminocyclopropane-1-carboxylic-acid

During the past decade, converging lines of evidence have linked the abnormal release or leak of excitatory amino acids to the neurodegeneration associated with a wide range of pathologies including cerebral ischemias, Huntington's disease, and AIDS dementia (Coyle and Robinson, 1987; Lipton, 1994; Meldrum, 1994). Pharmacological studies indicate that activation of both ionotropic and metabotropic glutamate receptors can substantially contribute to excitotoxic cell damage (Choi, 1992; Pizzi et al., 1993; Sheardown et al., 1993; Xue et al., 1994). Based on these findings, therapeutic strategies based on blunting or blocking glutamatergic transmission may be useful in treating a variety of neurodegenerative disorders.

Topics: AIDS Dementia Complex; Amino Acids; Amino Acids, Cyclic; Animals; Brain Ischemia; Humans; Huntington Disease; Nerve Degeneration; Neurons; Neuroprotective Agents; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Strychnine

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.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Behavior, Animal; Binding Sites; Cerebral Cortex; Glycine; Hippocampus; Kynurenic Acid; Male; Mice; Psychomotor Performance; Radioligand Assay; Receptors, N-Methyl-D-Aspartate; Strychnine; Tritium

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine sites of the N-methyl-D-aspartate (NMDA) channels and exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models used to evaluate potential antidepressants and anxiolytics, its effects on learning and memory are unknown. In the present study we investigated the effects of ACPC on spatial learning in the Morris water maze. On a schedule of 12 learning trials, one trial per day, mature male Wistar rats (3 months of age) rapidly acquired the task. Electroconvulsive shocks applied after each of the learning trials markedly inhibited the consolidation of spatial memory. Administration of either a muscarinic agonist, arecoline (1 mg/kg) or ACPC (250 or 400 mg/kg) 20 min before each of the learning trials did not affect the acquisition of spatial learning. Aged (16 months old) male Wistar rats demonstrated difficulties in the acquisition of spatial learning task. In these subjects, ACPC administered 20 min before each of the learning trials at a dose of 400, but not 250 mg/kg, facilitated the acquisition of spatial memory as indicated on trials 3-5. ACPC did not affect the strength of spatial memory as assessed at the end of conditioning, by measuring swimming behavior of rats in the pool with platform removed. It is suggested that ACPC may alleviate learning deficits observed in the elderly.

Topics: Age Factors; Amino Acids; Amino Acids, Cyclic; Animals; Arecoline; Electroshock; Glycine; Learning; Male; Maze Learning; Memory; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spatial Behavior; Strychnine; Time Factors

Using the conflict drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist and 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at strychnine-insensitive glycine receptors associated with the NMDA receptor complex, after their intraperitoneal (i.p.) and intrahippocampal (IHP) administration. CGP 37849, administered in doses of 1.25-5 mg/kg i.p., produced an anticonflict effect in a dose-dependent manner, but was inactive when injected in doses of 0.01-0.1 micrograms IHP. At the same time, when administered in higher doses (10 mg/kg i.p. or 0.3 micrograms IHP), that drug induced motor impairment. On the other hand, ACPC exhibited an anxiolytic-like activity after both i.p. (100-200 mg/kg) and IHP (3-30 micrograms) administration. These results, as well as the literature data on the lack of motor-impairing effects of ACPC, indicate that the latter drug seems to be more advantageous than CGP 37849 as a potential therapeutic agent in the treatment of anxiety disorders. Furthermore, they also show that the hippocampus may be one of the neuroanatomical sites of the anxiolytic-like effect of ACPC, but not of CGP 37849.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Anti-Anxiety Agents; Behavior, Animal; Brain; Conflict, Psychological; Dose-Response Relationship, Drug; Drinking Behavior; Electroshock; Excitatory Amino Acid Antagonists; Glycine Agents; Hippocampus; Injections; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Strychnine

The potential for compounds acting at the strychnine-insensitive glycine receptor to injure neurons was examined using induction of a 70 kDa heat shock protein (HSP-70) as a marker. HSP-70 was consistently detected in retrosplenial and cingulate cortices after MK-801 but not glycine drug treatment. Elsewhere in the cortex, mild diffuse HSP-70 immunoreactivity was detected following 7-chlorokynurenic acid. Following HA-966, intense hippocampal HSP-70 immunoreactivity was observed. These findings indicate that even after very high doses, drugs acting at the strychnine-insensitive glycine receptor are less likely to injure cingulate cortical neurons than other classes of NMDA antagonists.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Dizocilpine Maleate; Gyrus Cinguli; Heat-Shock Proteins; Hippocampus; Immunohistochemistry; Kynurenic Acid; Male; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Strychnine

Glutamate neurotoxicity was examined in cultured cerebellar granule neurons following both prolonged (20-24 h) and brief (45 min) exposure to compounds acting at strychnine-insensitive glycine receptors. Glutamate neurotoxicity was reduced in a concentration-dependent fashion by brief exposure to the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) and the competitive antagonist, 7-chlorokynurenic acid (7-CK) with a rank order efficacy: 7-CK > HA-966 > ACPC. Neither D-cycloserine (D-CS) nor glycine affected neurotoxicity produced by maximum glutamate concentrations, while glycine but not D-CS augmented the effects of submaximum glutamate concentrations. Prolonged exposure of cultures to either full (glycine) or partial agonists (ACPC, D-CS, HA-966) abolished the neuroprotective effects of ACPC and significantly diminished the neuroprotective effects of HA-966. In contrast, the neuroprotective effects of 7-CK were only marginally reduced by prolonged exposure to glycinergic ligands, while the neuroprotection afforded by compounds acting at other loci on the NMDA receptor complex (e.g. 2-amino-5-phosphonopentanoate (APV) and dizocilpine (MK-801)) were unaltered. These effects may represent homologous desensitization of the NMDA receptor complex at its strychnine-insensitive glycine receptor induced by prolonged exposure to glycinergic agonists and partial agonists. Nonetheless, levels of the NMDA receptor subunit zeta 1 mRNA were unaffected by prolonged exposure to ACPC, indicating the apparent desensitization could involve a post-translational modification of the NMDA receptor complex.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Analysis of Variance; Animals; Base Sequence; Blotting, Northern; Cells, Cultured; Cerebellum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Glutamic Acid; Glycine; Kinetics; Kynurenic Acid; Molecular Sequence Data; Neurons; Neurotoxins; Oligodeoxyribonucleotides; Polymerase Chain Reaction; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Strychnine; Time Factors

Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amino Acids; Amino Acids, Cyclic; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Kynurenic Acid; Male; Methamphetamine; Mice; Mice, Inbred Strains; Receptors, Glycine; Strychnine; Substantia Nigra

In the mammalian brain, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is coupled to a cation channel and a strychnine-insensitive glycine receptor. The present paper demonstrates the presence of NMDA receptor-coupled strychnine-insensitive glycine receptors in embryonic chick retina. Both glycine and 1-aminocyclopropanecarboxylic acid (ACPC) exhibited similar potencies (271 +/- 39 vs 247 +/- 39 nM, respectively) as inhibitors of strychnine-insensitive [3H]glycine binding to retinal membranes. Moreover, glycine and ACPC enhanced [3H]MK-801 binding to sites within the NMDA-coupled cation channel in retinal membranes with potencies comparable to those reported in rat brain. While the potency of ACPC was significantly higher than glycine (EC50 54 +/- 12 vs 256 +/- 57 nM, P < 0.02) in this measure, there were no significant differences in the maximum enhancement (efficacy) of [3H]MK-801 binding by these compounds. Since glycine appears to be required for the operation of NMDA-coupled cation channels, we examined the effects of glycine and ACPC on NMDA-induced acute excytotoxicity in the 14-day embryonic chick retina. Histological evaluation of retina revealed that either ACPC (10-100 microM) or glycine (200 microM) attenuated NMDA-induced (200 microM) retinal damage and a combination of these agents produced an enhanced protection against acute NMDA toxicity. ACPC (100 microM), but not MK-801 (1 microM) also afforded a modest protection against kainate-induced (25 microM) retinal damage. These findings demonstrate that while strychnine-insensitive glycine receptors are present in embryonic chick retina, occupation of these sites does not augment the cytotoxic actions of NMDA. Moreover, the ability of ACPC and glycine to attenuate NMDA-induced cytotoxicity does not appear to be mediated through occupation of these sites.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Chick Embryo; Dizocilpine Maleate; Drug Resistance; gamma-Aminobutyric Acid; N-Methylaspartate; Neurotoxins; Receptors, Glycine; Receptors, Neurotransmitter; Retina; Strychnine

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine receptors that exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models commonly used to evaluate potential antidepressants (forced swim) and anxiolytics (plus-maze), the zwitterionic character of this compound could limit both penetration into the central nervous system and oral availability. The present experiments were designed to determine the duration of action of ACPC, its efficacy following oral administration, and to compare these effects with the more lipophilic ACPC methyl ester. Parenterally and orally administered ACPC were equipotent in reducing immobility in the forced swim test, an action manifested for at least 6 h. Both orally and parenterally administered ACPC methyl ester were approximately 3.3-fold more potent than ACPC in the forced swim test. In the elevated plus-maze, both ACPC and ACPC methyl ester were active for 1-2 h after parenteral administration. These findings suggest that 1-aminocyclopropanecarboxylates may constitute a novel class of antidepressant/anxiolytic agents.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Anti-Anxiety Agents; Antidepressive Agents; Cerebral Cortex; Dose-Response Relationship, Drug; Electroshock; Glycine; Immobilization; Male; Mice; Motor Activity; Strychnine; Swimming; Synaptosomes

Inescapable, but not escapable, stress inhibits the induction of Long Term Potentiation (LTP) in the CA1 region of hippocampus, a process that is dependent upon activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Since inescapable stress also produces a syndrome of behavioral depression sensitive to clinically effective antidepressants, we examined the actions of functional antagonists at the NMDA receptor complex in animal models commonly used to evaluate potential antidepressants. A competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid [AP-7]), a non-competitive NMDA antagonist (Dizolcipine [MK-801]), and a partial agonist at strychnine-insensitive glycine receptors (1-aminocylopropanecarboxylic acid [ACPC]) mimicked the effects of clinically effective antidepressants in these models. These findings indicate that the NMDA receptor complex may be involved in the behavioral deficits induced by inescapable stress, and that substances capable of reducing neurotransmission at the NMDA receptor complex may represent a new class of antidepressants. Based on these findings, the hypothesis that pathways subserved by the NMDA subtype of glutamate receptors are involved in the pathophysiology of affective disorders may have heuristic value.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Antidepressive Agents; Behavior, Animal; Brain Chemistry; Dizocilpine Maleate; Dose-Response Relationship, Drug; Imipramine; Immobilization; Male; Mice; Mice, Inbred C57BL; Motor Activity; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Stress, Psychological; Strychnine; Swimming; Synaptic Transmission

1-Aminocyclopropane carboxylic acid (ACPC) competitively inhibited (IC50, 38 +/- 7 nM) [3H]glycine binding to rat forebrain membranes but did not affect [3H]strychnine binding to rat brainstem/spinal cord membranes. Like glycine, ACPC enhanced 3H-labelled (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([3H]MK-801) binding to N-methyl-D-aspartate receptor-coupled cation channels (EC50, 135 +/- 76 nM and 206 +/- 78 nM for ACPC and glycine, respectively) but was approximately 40% less efficacious in this regard. The maximum increase in [3H]MK-801 binding produced by a combination of ACPC and glycine was not different from that elicited by glycine, but both compounds potentiated glutamate-stimulated [3H]MK-801 binding. These findings indicate that ACPC is a potent and selective ligand at the glycine modulatory site associated with the N-methyl-D-aspartate receptor complex.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Binding, Competitive; Brain Stem; Cations; Dibenzocycloheptenes; Diencephalon; Dizocilpine Maleate; Glutamates; Glutamic Acid; Glycine; Ion Channels; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord; Strychnine; Synaptic Membranes; Telencephalon

The effects of 1-aminocyclopropanecarboxylic acid were investigated on performance in an elevated plus-maze. This compound is a high-affinity, partial agonist ligand at strychnine-insensitive glycine receptors of the N-methyl-D-aspartate receptor complex. Like chlordiazepoxide, 1-aminocyclopropanecarboxylic acid increased in a dose-dependent manner both the percent entries into and the percent time spent in the open arms of the plus-maze. However, 1-aminocyclopropanecarboxylic acid was significantly less efficacious than chlordiazepoxide in these measures and increased, while chlordiazepoxide decreased, the time spent in the middle platform of the plus-maze. These findings indicate that ligands acting through strychnine-insensitive glycine receptors on the N-methyl-D-aspartate receptor complex may represent a new class of anxiolytic agents with a profile which differs from the benzodiazepines.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Anti-Anxiety Agents; Conflict, Psychological; Male; Mice; Receptors, Glycine; Receptors, Neurotransmitter; Strychnine; Task Performance and Analysis

1-Aminocyclopropanecarboxylic acid is a potent and selective ligand for the glycine modulatory site on the N-methyl-D-aspartate receptor complex. This compound blocks (ED50 234 mg/kg) the convulsions and deaths produced by N-methyl-D-aspartate (125 mg/kg) in a dose dependent fashion. In contrast, 1-aminocyclopropanecarboxylic acid does not protect mice against convulsions induced by pentylenetetrazole (80 mg/kg), strychnine (2 mg/kg), bicuculline (6 mg/kg), or maximal electroshock (50 mA, 0.2 s), and does not impair motor performance on either a rotarod or horizontal wire at doses of up to 2 g/kg. The methyl- and ethyl- esters of 1-aminocyclopropanecarboxylic acid are 5- and 2.3-fold more potent, respectively, than the parent compound in blocking the convulsant and lethal effects of N-methyl-D-aspartate. However, these esters are several orders of magnitude less potent (IC50 greater than 40 microM) than 1-aminocyclopropanecarboxylic acid as inhibitors of strychnine-insensitive [3H] glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action. These findings suggest that 1-aminocyclopropanecarboxylates may be useful in the treatment of neuropathologies associated with excessive activation of N-methyl-D-aspartate receptor coupled cation channels.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Anticonvulsants; Aspartic Acid; Bicuculline; Dose-Response Relationship, Drug; Electroshock; Male; Mice; N-Methylaspartate; Pentylenetetrazole; Rats; Rats, Inbred Strains; Strychnine; Synaptic Membranes