Abstract
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.
Similar content being viewed by others
References
Bennett D, Amrick C (1986) 2-Amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam, Life Sci 39:2455–2461
Benveniste M, Clements J, Vyklicky L, Mayer M (1990) A kinetic analysis of the modulation of N-methyl-d-aspartic acid receptors by glycine in mouse cultured hippocampal neurones. J Physiol (London) 428:333–357
Boast C, Pastor G, Gerhardt S, Hall N, Liebman J (1988) Behavioral tolerance and sensitization to CGS 19755, a competitive N-methyl-d-aspartate receptor antagonist. J Pharmacol Exp Ther 247:556–561
Collingridge G, Kehl S, McLennan H (1983) Excitatory amino acid in synaptic transmission in the Schaffer collateral commissural pathway of the rat hippocampus. J Physiol 334:33–46
Compton R, Hood W, Monahan J (1991) Evidence for a functional coupling of the NMDA and glycine recognition sites in synaptic plasma membranes. Eur J Pharmacol 188:63–70
Desan P, Silbert L, Maier S (1988) Long-term effects of inescapable stress on daily running activity and antagonism by desipramine, Pharmacol Biochem Behav 30:21–29
Evans R, Francis A, Jones A, Smith D, Watkins J (1982) The effects of a series of ω-phosphonic-α-carboxylic amino acids on electrically evoked and amino acid induced responses in isolated spinal cord preparations. Br J Pharmacol 75:65–75
Evoniuk G, Hertzman R, Skolnick P (1991) A rapid method for detecting phencyclidine-like dissociative anesthetics in mice. Psychopharmacology 105:125–128
Harris E, Ganong A, Cotman C (1984) Long term potentiation in the hippocampus involves activation in N-methyl-d-aspartate receptors. Brain Res 323:132–137
Heninger G, Charney D (1987) Mechanism of action of antidepressant treatments: implications for the etiology and treatment of depressived disorders. In: Meltzer H (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 535–544
Huettner J, Bean B (1988) Block of N-methyl-d-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci USA 85:1307–1311
Johnson K, Jones S (1990) Neuropharmacology of phencyclidine: basic mechanisms and therapeutic potential. Annu Rev Pharmacol Toxicol 30:707–750
Johnson K, Snell L, Sacaan L, Jones S (1989) Pharmacological regulation of the phencyclidine-binding site associated with the N-methyl-d-aspartate receptor-operated ion channel. Drug Dev Res 17:281–297
Kemp J, Priestley T (1991) Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N-methyl-d-aspartate receptor agonist responses in rat cultured cortical neurons. Mol Pharmacol 39:666–670
Lehmann J, Schneider J, McPherson S, Murphy D, Bernard P, Tsai C, Bennett D, Pastor G, Steel D, Boehm C, Cheney D, Liebman J, Williams M, Wood P (1987) CPP, a selective N-methyl-d-aspartate (NMDA)-type receptor antagonist: characterization in vitro and in vivo. J Pharmacol Exp Ther 240:737–746
Leshner A, Remler A, Bigeon A, Samuel D (1979) Effects of desmethylimipramine on learned helplessness. Psychopharmacology 66:207–208
Lister R (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185
Marvizon J, Lewin A, Skolnick P (1989) 1-Aminocyclopropane carboxylic acid: a potent and selective ligand for the glycine modulatory site of the N-methyl-d-aspartate receptor complex. J Neurochem 52:992–994
Monaghan D, Holets V, Toy D, Cotman C (1983) Anatomical distribution of four anatomically [3H]glutamate binding sites. Nature 306:176–179
Monaghan D, Yao D, Olverman H, Watkins J, Cotman C (1984) Autoradiography ofd-2-[3H]amino-5-phosphonopentanoate binding sites in rat brain. Neurosci Lett 52:253–258
Monaghan D, Olverman H, Nguyen L, Watkins J, Cotman C (1988) Two classes of N-methyl-d-aspartate recognition sites: differential distribution and differential regulation by glycine. Proc Natl Acad Sci USA 85:9836–9840
Oswald I, Brezinova V, Dunleavy D (1972) On the slowness of action of tricyclic antidepressant drugs. Br J Psychiatry 120:673–677
Paul I, Trullas R, Skolnick P, Nowak G (1992) Downregulation of cortical β-adrenoceptors by chronic treatment with functional antagonists of the NMDA receptor complex. Psychopharmacology 106:285–287
Petty F, Sherman A (1980) Reversal of learned helplessness by imipramine, Commun Psychopharmacol 3:371–373
Porsolt R (1981) Behavioral despair. In: Enna S, Malick J, Richelson E (eds) Antidepressants: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 121–139
Porsolt R, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336
Robinson M, Coyle J (1987) Glutamate and related excitatory amino neurotransmitters: from basic science to clinical application. FASEB J 1:446–455
Rogawski M, Thurkauf A, Rice K, Jacobsen A, Ffrench-Mullen J (1988) Anticonvulsant activity of phencyclidine analogs: structural modifications resulting in enhanced seizure protection relative to motor side effects. In: Cavalheiro EA, Lehmann J, Turski L (eds) Frontiers in excitatory amino acid research. Liss, New York, pp 227–230
Shanks N, Anisman H (1989) Strain-specific effects of antidepressants on escape deficits induced by inescapable shock, Psychopharmacology 99:122–128
Shors T, Seib T, Levine S, Thompson R (1989) Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus. Science 244:224–226
Sills M, Fagg G, Pozza M, Angst C, Brundish D, Hurt S, Wilusz E, Williams M (1991) [3H]CGP 39653: a new N-methyl-d-aspartate antagonist radioligand with low nanomolar affinity in rat brain. Eur J Pharmacol 192:19–24
Skolnick P, Marvizon J, Jackson B, Monn J, Rice K, Lewin A (1989) Blockade of N-methyl-d-aspartate induced convulsions by 1-aminocyclopropanecarboxylates. Life Sci 45:1647–1655
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370
Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185:1–10
Trullas R, Jackson B, Skolnick P (1989) 1-Aminocyclopropanecarboxylic acid, a ligand of the strychnine-insensitive glycine binding site exhibits anxiolytic properties. Pharmacol Biochem Behav 34:313–316
Trullas R, Folio T, Young A, Miller R, Boje K, Skolnick P (1991) 1-Aminocyclopropanecarboxylates exhibit antidepressant and anxiolytic actions in animal models. Eur J Pharmacol (in press)
Watson G, Lanthorn T (1990) Pharmacological characteristics of cyclic homologues of glycine at the N-methyl-d-aspartate receptor associated glycine site. Neuropharmacology 29:727–730
Winslow J, Insel T, Trullas R, Skolnick P (1990) Rat pup isolation calls are reduced by functional antagonists of the NMDA receptor complex. Eur J Pharmacol 190:11–22
Wong E, Kemp J, Priestley T, Knight A, Woodruff G, Iversen L (1986) The anticonvulsant MK-801 is a potent N-methyl-d-aspartate antagonist. Proc Natl Acad Sci USA 83:7104–7108
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Skolnick, P., Miller, R., Young, A. et al. Chronic treatment with 1-aminocyclopropanecarboxylic acid desensitizes behavioral responses to compounds acting at the N-methyl-d-aspartate receptor complex. Psychopharmacology 107, 489–496 (1992). https://doi.org/10.1007/BF02245261
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245261