Chronic treatment with 1-aminocyclopropanecarboxylic acid desensitizes behavioral responses to compounds acting at the N-methyl-D-aspartate receptor complex.
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.
Skolnick
P
P
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD 20892.
Miller
R
R
Young
A
A
Boje
K
K
Trullas
R
R
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology*; D000598:Amino Acids, Cyclic; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013550:Swimming
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D000927:Anticonvulsants; D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; C023863:1-aminocyclopropane-1-carboxylic acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C031231:2-amino-7-phosphonoheptanoic acid