cgp-37849 and 1-aminocyclopropane-1-carboxylic-acid

In this paper we examined the effect of flumazenil (Ro 15-1788, 10 mg/kg), a benzodiazepine receptor antagonist, on the anticonflict 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 glycine(B) receptors, in the Vogel conflict drinking test in rats. The effect of flumazenil on the anxiolytic-like (in the plus-maze test) and the anticonvulsant (in the maximal electroshock-induced seizures) activities of CGP 37849 in rats was also studied. Diazepam was used as a reference drug. CGP 37849 (2. 5-5 mg/kg), ACPC (50-200 mg/kg) and diazepam (2.5-5 mg/kg) significantly and dose-dependently increased the number of shocks accepted during experimental sessions in the conflict drinking test. Flumazenil partly but significantly reduced the anticonflict effect of CGP 37849, and it fully blocked the anticonflict effect of ACPC and diazepam. CGP 37849 (2.5-5 mg/kg) and diazepam (2.5-5 mg/kg) were also active in the plus-maze test, as they significantly increased the percentage of the time spent in and entries into the open arms of the plus-maze, both those effects having been antagonized by flumazenil. Flumazenil alone was inactive in both the conflict drinking and the plus-maze tests. In the maximal electroshock-induced seizures, both CGP 37849 (2.5-5 mg/kg) and diazepam (5-10 mg/kg) produced anticonvulsant effects, of which only that of diazepam was antagonized by flumazenil. The results of the present study showing antagonism of flumazenil towards the anxiolytic-like effects of CGP 37849 and ACPC suggest involvement of benzodiazepine receptors in such an activity of the NMDA and glycine(B) receptor ligands, respectively, which may be due to a possible interaction between NMDA and GABA/benzodiazepine systems. The lack of effect of the benzodiazepine antagonist on the anticonvulsant activity of CGP 37849 indicates that involvement of benzodiazepine receptors in the pharmacological action of the NMDA antagonist is not a general phenomenon.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Anti-Anxiety Agents; Conflict, Psychological; Diazepam; Dose-Response Relationship, Drug; Drinking Behavior; Electroshock; Excitatory Amino Acid Antagonists; Flumazenil; GABA-A Receptor Antagonists; Male; Maze Learning; Rats; Rats, Wistar; Seizures

Using the forced swimming test in rats (Porsolt test), we examined the antidepressant-like activity of 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at strychnine-insensitive glycine receptors associated with the N-methyl-D-aspartate (NMDA) receptor complex, and of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive NMDA receptor antagonist, after their intraperitoneal (i.p.) and intrahippocampal (i.hp.) administration. ACPC (200-400 mg/kg) and CGP 37849 (0.625-5 mg/kg), administered i.p., produced a dose-dependent and significant reduction of the immobility time in the forced swimming test. A similar effect was also observed in i.hp. administration of ACPC (10 and 30 micrograms) and CGP 37849 (0.03 and 0.1 micrograms). Imipramine, used as a reference drug, significantly shortened the immobility time after both i.p. (30 and 40 mg/kg) and i.hp (0.1 and 0.3 micrograms) administration. The compounds studied, administered in doses effective in the forced swimming test, did not change the exploratory activity of the rats, evaluated by an open field test. The present results indicate that, like imipramine, ACPC and CGP 37849 exhibit an antidepressant-like activity in the forced swimming test in rats; moreover, they seem to show the hippocampus may be one of the neuroanatomical sites involved in this effect.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Antidepressive Agents; Behavior, Animal; Male; Motor Activity; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

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

A conditioned place preference paradigm was used to assess the potential rewarding properties of the uncompetitive NMDA receptor antagonist, MK-801 (dizolcipine), the two competitive NMDA receptor antagonists, CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentonoic acid) and its (R)-enantiomer CGP 40116, as well as the partial agonist at strychnine-insensitive glycine receptors, ACPC (1-aminocyclopropanecarboxylic acid). MK-801 (0.3 mg/kg), CGP 37849 (1.25-10 mg/kg) and CGP 40116 (1.25-10 mg/kg), administered in association with either the initially non-preferred or initially preferred side of the two-arm chamber, caused a significant increase in the time spent on that side in a post-conditioning test. In contrast, ACPC did not support the conditioned place preference. Thus, the time spent on the drug-associated side following conditioning with ACPC (50-400 mg/kg) did not significantly differ from that measured in the pre-conditioning test, irrespective of whether it was associated with the initially non-preferred black side or the initially preferred white side. These results are consistent with both clinical and pre-clinical data demonstrating differences in psychopharmacological properties among compounds acting at the multiple, allosteric regulatory sites on the NMDA receptor complex. Moreover, these results indicate that the abuse potential of ACPC, which acts as a functional NMDA receptor antagonist, may be lower than that of either uncompetitive or competitive NMDA receptor antagonists.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Binding, Competitive; Conditioning, Operant; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

Sound-induced seizures in genetically epilepsy-prone rats were used to compare the anticonvulsant effect of phenytoin and diazepam with compounds which decrease glutamatergic neurotransmission including excitatory amino acid antagonists acting at N-methyl-D-aspartate (NMDA) receptors: D(-)CPPene, CGP 37849 and MK 801 or at the glycine/NMDA site: ACPC (1-aminocyclopropane-dicarboxylic acid) (partial agonist) or non-NMDA receptors: NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]-quinoxaline.Li) and GYKI 52466 (1-(aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepin e.HCl) or acting at sodium channels to decrease glutamate release: lamotrigine and BW 1003C87 (5(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonate). ED50 values against clonic seizures (in mumol/kg at the time of peak anticonvulsant effect) were: phenytoin 30.5 (2 h), diazepam 0.5 (0.5 h), MK 801 0.01 (4 h), D(-)CPPene 1.9 (4 h), CGP 37849 2 (1 h), GYKI 52466 24 (0.25 h), NBQX 40 (0.5 h), ACPC 1053 (0.5 h), BW 1003C87 2.2 (1 h), lamotrigine 4.8 (4 h). BW 1003C87, lamotrigine, MK 801, phenytoin, diazepam and CGP 37849 had the most favourable therapeutic indices (rotarod locomotor deficit ED50/anticonvulsant ED50).

Topics: 2-Amino-5-phosphonovalerate; Acoustic Stimulation; Amino Acids; Amino Acids, Cyclic; Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Epilepsy; Female; Lamotrigine; Male; Motor Activity; Phenytoin; Pyrimidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors; Triazines