Abstract
The study compares effects of the competitive and non-competitive NMDA receptor antagonists, CGP 40116 and MK-801 respectively, on the metabolism of dopamine and on the density of D-1 and D-2 dopaminergic receptors in the rat ventral tegmental area and substantia nigra. The effects of CGP 40116 were tested in a range of doses which either were devoid of or had locomotor- or stereotypy-stimulating effects. It was found that (1) CGP 40116 given in a dose of 5 mg/kg enhanced the locomotor activity of rats and evoked a stereotypy-like activity; doses of 1.25 and 2.5 mg/kg were devoid of such effects; (2) CGP 40116 (5 mg/kg) enhanced the concentrations of dopamine, DOPAC and HVA in the ventral tegmental area, whereas the lowest dose, 1.25 mg/kg was without effect; a dose of 2.5 mg/kg increased the concentration of dopamine only; the only effect of CGP 40116 (5 mg/kg) observed in substantia nigra, was an increase in dopamine concentration; its doses of 1.25 and 2.5 mg/kg were ineffective. (3) MK-801 (0.2 and 0.4 mg/kg) enhanced the concentrations of dopamine, DOPAC and HVA in both structures. A dose of 0.1 mg/kg increased the dopamine concentration only. The effects of MK-801 in substantia nigra were quantitatively weaker than those observed in ventral tegmental area. (4) Both CGP 40116 (5 mg/kg) and MK-801 (0.4 mg/kg) evolved alterations in the density of dopaminergic receptors. D-2 receptors, were up-regulated by MK-801 in ventral tegmental area and subregions of substantia nigra, i.e. pars compacta and pars reticulata, whereas CGP 40116 evoked similar effects in ventral tegmental area only. D-1 receptors in pars compacta and pars reticulata of substantia nigra were down-regulated after administration of either drug.
It is concluded that competitive NMDA receptor antagonists in doses which evoke hyperlocomotion and stereotypy-like activity, may have a substantial impact on the dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra, similar to that described for MK-801, a non-competitive NMDA receptor antagonist. The obtained results may suggest that CGP 40116 and, possibly, other competitive NMDA antagonists may have dopaminomimetic properties, and that their clinical potentials may be limited by the risk of evoking dopamine-dependent psychotomimetic and abusing effects, similar to those described for MK-801.
Similar content being viewed by others
References
Biron D, Dauphin C, Di Paolo T (1992) Effects of adrenalectomy and glucocorticoids on rat brain dopamine receptors. Neuroendocrinology 55:468–476
Bubser M, Keseberg U, Notz PK, Schmidt WJ (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol 229:75–82
Carter CJ (1982) Topographical distribution of possible glutamatergic pathways from the frontal cortex to the striatum and substantia nigra in rats. Neuropharmacology 21:379–383
Christie MJ, Bridge S, James LB, Beart PM (1985a) Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area. Brain Res 333:169–172
Christie MJ, James LB, Beart PM (1985b) An excitant amino acid projection from the medial prefrontal cortex to the anterior part of nucleus accumbens in the rat. J Neurochem 45:477–482
Dall'Olio R, Gandolfi O, Montanaro M, (1992) Effect of chronic treatment with dizocilpine (MK-801) on the behavioral response to dopamine receptor agonists in the rat. Psychopharmacology (Berl) 107:591–594
Deutch AY, Tam SY, Freeman AS, Bowers MBJr, Roth RH (1987) Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response. Eur J Pharmacol 134:257–264
Dragunow M, Faull RL (1990) MK801 induces c-fos protein in thalamic and neocortical neurons of rat brain. Neurosci Lett 113:144–150
Fagg GE, Olpe HR, Pozza MF, Baud J, Steinmann M, Schmutz M, Portet C, Baumann P, Thedinga K, Bittiger H, et al (1990) CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity. Br J Pharmacol 99:791–797
French ED, Ceci A, (1990) Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons. Neurosci Lett 119:159–162
French ED, Ferkany J, Abreu M, Levenson S (1991) Effects of competitive N-methyl-D-aspartate antagonists on midbrain dopamine neurons: an electrophysiological and behavioral comparison to phencyclidine. Neuropharmacology 30:1039–1046
French ED, Mura A, Wang T (1993) MK-801, phencyclidine (PCP) and PCP-like drugs increase burst firing in rat A10 dopamine neurons: comparison to competitive NMDA antagonists. Synapse 13:108–116
Gandolfi O, Dall'Olio R (1993) Chronic treatment with MK-801 decreases D2 dopamine receptor function in rat striatum. Pharmacol Biochem Behav 44:683–687
Gass P, Herdegen T, Bravo R, Kiessling M (1993) Induction and suppression of immediate early genes in specific rat brain regions by the non-competitive N-methyl-D-aspartate receptor antagonist MK-801. Neuroscience 53:749–758
Girault JA, Halpain S, Greengard P (1990) Excitatory amino acid antagonists and Parkinson's disease. Trends Neurosci. 13:325–327
Goodwin P, Starr BS, Starr MS (1992) Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801. J Neural Transm Park Dis Dement Sect 4:15–26
Halpain S, Girault JA, Greengard P (1990) Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. Nature 343:369–372
Hervé D, Trovero F, Blanc G, Thierry AM, Glowinski J, Tassin JP (1989) Nondopaminergic prefrontocortical efferent fibers modulate D1 receptor denervation supersensitivity in specific regions of the rat striatum. J Neurosci 9:3699–3708
Hiramatsu M, Cho AK, Nabeshima T (1989) Comparison of the behavioral and biochemical effects of the NMDA receptor antagonists, MK-801 and phencyclidine. Eur J Pharmacol 166:359–366
Hondo H, Yonezawa Y, Nakahara T, Nakamura K, Hirano M, Uchimura H, Tashiro N (1994) Effect of phencyclidine on dopamine release in the rat prefrontal cortex; an in vivo microdialysis study. Brain Res. 633:337–342
Kabuto HI, Yokoi I, Mizukawa K, Mori A. (1989) Effects of an N-methyl-D-aspartate- receptor agonist and its antagonist CPP on the levels of dopamine and serotonin metabolites in rat striatum collected in vivo by using a brain dialysis technique. Neurochem Res 14:1075–1081
Kalivas PW (1993) Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res Brain Res Rev. 18:75–113
Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug-and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16:223–244
Klockgether T, Turski L (1990) NMDA antagonists potentiate anti-parkinsonian actions of L-dopa in monoamine-depleted rats. Ann Neurol 28:539–546
Kobayashi K, Inoue O, (1993) An increase in the in vivo binding of SCH 23390 induced by MK-801 in the mouse striatum. Neuropharmacology 32:341–348
Koek W, Colpaert FC (1990) Selective blockade of N-methyl-D-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther 252:349–357
Koek W, Woods JH, Winger GD (1988) MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther 245:969–974
Liljequist S, Ossowska K, Grabowska Anden M, Anden NE (1991) Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice. Eur J Pharmacol 195:55–61
Löscher W, Honack D (1991a) The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin IA receptors. J Pharmacol Exp Ther 257:1146–1153
Löscher W, Honack D (1991b) Anticonvulsant and behavioral effects of two novel competitive N-methyl-D-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine. J Pharmacol Exp Ther 256:432–440
Löscher W, Honack D (1992) The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems. Eur J Pharmacol 215:199–208
Löscher W, Annies R, Honack D (1991) The N-methyl-D-aspartate receptor antagonist MK-801 induces increases in dopamine and serotonin metabolism in several brain regions of rats. Neurosci. Lett 128:191–194
Löscher W, Annies R, Honack D (1993) Comparison of competitive and uncompetitive NMDA receptor antagonists with regard to monoaminergic neuronal activity and behavioural effects in rats. Eur. J Pharmacol 242:263–274
Maj J, Rogóź Z, Skuza G (1991) Locomotor hyperactivity induced by MK-801 in rats. Pol J Pharmacol Pharm 43:449–458
Mansbach RS, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology. 2:299–308
Mansour A, Meador Woodruff JH, Bunzow JR, Civelli O, Akil H, Watson SJ, (1990) Localization of dopamine D2 receptor mRNA and Dl and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor auto radiographic analysis. J Neurosci 10:2587–2600
Mansour A, Meador Woodruff JH, Zhou Q, Civelli O, Akil H, Watson SJ (1992) A comparison of D1 receptor binding and mRNA in rat brain using receptor autoradiographic and in situ hybridization techniques. Neuroscience 46:959–971
Meador Woodruff JH, Mansour A, Healy DJ, Kuehn R, Zhou QY, Bunzow JR, Akil H, Civelli O, Watson SJ (1991) Comparison of the distributions of D1 and D2 dopamine receptor mRNAs in rat brain. Neuropsychopharmacology 5:231–242
Meldrum BS (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68:113–122
Micheletti G, Lannes B, Haby C, Borrelli E, Kempf E, Warter JM, Zwiller J (1992) Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum. Brain Res Mol Brain Res 14:363–368
Morelli M, Di Chiara G (1990) MK-801 potentiates dopaminergic D1 but reduces D2 responses in the 6-hydroxydopamine model of Parkinson's disease. Eur J Pharmacol 182:611–612
Morelli M, Fenu S, Pinna A, Di Chiara G (1992) Opposite effects of NMDA receptor blockade on dopaminergic D1-and D2-mediated behavior in the 6-hydroxydopamine model of turning: relationship with c-fos expression. J Pharmacol Exp Ther 260:402–408
Olney JW (1989) Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry 26:505–525
Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs [see comments]. Science 244:1360–1362
Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254:1515–1518
Palkowits M, Brownstein MJ (1988) Maps and guide to microdissection of the rat brain. Elsevier, New York Amsderdam London
Paul IA, Trullas R, Skolnick P, Nowak G (1992) Down-regulation of cortical beta-adrenoceptors by chronic treatment with functional NMDA antagonists. Psychopharmacology (Berl) 106:285–287
Pechnick RN, George R, Poland RE (1989) Characterization of the effects of the acute and repeated administration of MK-801 on the release of adrenocorticotropin corticosterone and prolactin in the rat. Eur J Pharmacol 164:257–263
Porceddu ML, Giorgi O, Ongini E, Mele S, Biggio G (1986) 3H-SCH 23390 binding sites in the rat substantia nigra: evidence for a presynaptic localization and innervation by dopamine. Life Sci 39:321–328
Pozza MF, Olpe HR, Brugger F, Fagg GE (1990) Electrophysiological characterization of a novel potent and orally active NMDA receptor antagonist: CGP 37849 and its ethylester CGP 39551. Eur J Pharmacol 182:91–100
Qin ZH, Zhou LW, Weiss B (1994) D2 dopamine receptor messenger RNA is altered to a greater extent by blockade of glutamate receptors than by blockade of dopamine receptors. Neuroscience 60:97–114
Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL (1990) Interactions of phencyclidine receptor agonist MK-801 with dopaminergic system: regional studies in the rat. J Neurochem 54:1157–1162
Rao TS, Contreras PC, Cler JA, Mick SJ, Dilworth VM, Iyengar S, Monahan JB, Wood PL (1991) Contrasting neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate-coupled and -uncoupled PCP recognition sites. J Neurochem 56:890–897
Rogawski MA (1992) The NMDA receptor, NMDA antagonists and epilepsy therapy. A status report. Drugs 44:279–292
Savasta M, Dubois A, Benavides J, Scatton B (1986a) Different neuronal location of SCH 23390 binding sites in pars reticulata and pars compacta of the substantia nigra in the rat. Neurosci Lett 72:265–271
Savasta M, Dubois A, Scatton B (1986b) Autoradiographic localization of Dl dopamine receptors in the rat brain with SCH 23390. Brain Res 375:291–301
Schmutz M, Porter C, Jeker A, Klebs K, Vassout A, Allgeier H, Heckendorn R, Fagg GE, Olpe HR, van Riezen H (1990) The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent, orally-active anticonvulsants in rodents. Naunyn Schmiedeberg's Arch Pharmacol 342:61–66
Sesack SR, Deutch AY, Roth RH, Bunney BS (1989) Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin J Comp Neurol 290:213–242
Sharp FR, Butman M, Koistinaho J, Aardalen K, Nakki R, Massa SM, Swanson RA, Sagar SM (1994) Phencyclidine induction of the hsp 70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels. Neuroscience 62:1079–1092
Sveinbjornsdottir S, Sander JK, Upton D, Thompson PJ, Patsalos PN, Hirt D, Emre M, Lowe D, Duncan JS (1993) The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res 16:165–174
Svensson A, Pileblad E, Carlsson M (1991) A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice. J Neural Transm 85:117–129
Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–87
Węzony K, Czyrak A (1994) The role of corticosteroids in the acquisition of sensitization to locomotor stimulant effects of MK-801. Brain Res 657:351–356
Węzony K, Gołembiowska K, Klimek V (1993a) MK-801-induced symptoms of sensitization. The lack of correlation with the extracellular concentration of dopamine in the rat prefrontal cortex. Brain Res 625:333–336
Węzony K, Klimek V, Gołembiowska K (1993b) MK-801 elevates the extracellular concentration of dopamine in the rat prefrontal cortex and increases the density of striatal dopamine D-1 receptors. Brain Res 622:325–329
Węzony K, Gołembiowska K, Zazula M (1994) Differential effects of CGP 37849 and MK-801, competitive and noncompetitive NMDA antagonists, with respect to the modulation of sensorimotor gating and dopamine outflow in the prefrontal cortex in rats. Naunyn Schmiedeberg's Arch Pharmacol 350:555–562
Willetts J, Balster RL, Leander JD (1990) The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 11:423–428
Wolf ME, Khansa MR (1991) Repeated administration of Mk-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine. Brain Res 562:164–168
Wolf ME, White FJ, Hu XT (1993) Behavioural sensitization to MK-801 (dizocilpine): neurochemical and electropbysiological correlates in mesoaccumbal dopamine system. Behavioural Pharmacol 4:429–442
Wolf ME, White FJ, Hu XT (1994) MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine. J Neurosci 14:1735–1745
Wong EH, Knight AR, Woodruff GN (1988) [3H]MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes. J Neurochem 50:274–281
Zhang J, Chiodo LA, Freeman AS (1992) Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons. Brain Res 590:153–163
Zhang J, Chiodo LA, Freeman AS (1993) Effects of phencyclidine, MK-801 and 1,3-di(2-tolyl)guanidine on non-dopaminergic midbrain neurons. Eur J Pharmacol 230:371–374
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Węzony, K., Czyrak, A., Mackowiak, M. et al. The impact of a competitive and a non-competitive NMDA receptor antagonist on dopaminergic neurotransmission in the rat ventral tegmental area and substantia nigra. Naunyn-Schmiedeberg's Arch Pharmacol 353, 517–527 (1996). https://doi.org/10.1007/BF00169171
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00169171