pmc logo image
Logo of brjpharmJournal URL: http://www3.interscience.wiley.com/journal/121548564/home
Journal List > Br J Pharmacol > v.119(4); Oct 1996

Formats:
Br J Pharmacol. 1996 October; 119(4): 751–757.
PMCID: PMC1915756
Copyright notice
Inhibition by memantine of the development of persistent oral dyskinesias induced by long-term haloperidol treatment of rats.
O. A. Andreassen, T. O. Aamo, and H. A. Jøorgensen
Department of Physiology, Section Sandviken Hospital, University of Bergen, Norway.
Abstract
1. Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if neuroleptic-induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1-amino-3,5-dimethyladamantane), was studied in a rat model of TD. 2. In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg-1 day-1, and on the seventh day they received one injection of either haloperidol 1.0 mg kg-1 i.p. or saline i.p. In a subsequent long-term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg-1 every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long-term treatment. 3. In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidol-induced increase in the putative TD-analogue vacuous chewing movements (VCM). 4. In the long-term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dose-dependently increased VCM and moving during long-term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co-treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects. 5. These results suggest that long-lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.
Full text
Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
 
icon of scanned page 751
751
icon of scanned page 752
752
icon of scanned page 753
753
icon of scanned page 754
754
icon of scanned page 755
755
icon of scanned page 756
756
icon of scanned page 757
757
 
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
  • Ahlenius S, Hillegaart V. Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs: a comparison between the effects produced by pre- and post-synaptic inhibition of dopaminergic neurotransmission. Pharmacol Biochem Behav. 1986 May;24(5):1409–1415. [PubMed]
  • Andreassen OA, Jørgensen HA. GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats. Psychopharmacology (Berl). 1994 Dec;116(4):517–522. [PubMed]
  • Andreassen OA, Jørgensen HA. The mitochondrial toxin 3-nitropropionic acid induces vacuous chewing movements in rats. Implications for tardive dyskinesia? Psychopharmacology (Berl). 1995 Jun;119(4):474–476. [PubMed]
  • Andreassen OA, Jørgensen HA. The rat model of tardive dyskinesia: relationship between vacuous chewing movements and gross motor activity during acute and long-term haloperidol treatment. Life Sci. 1995;57(24):2263–2272. [PubMed]
  • Barnes CA, Danysz W, Parsons CG. Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci. 1996 Mar;8(3):565–571. [PubMed]
  • Beal MF, Hyman BT, Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci. 1993 Apr;16(4):125–131. [PubMed]
  • Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol. 1989 Aug 3;166(3):591–592. [PubMed]
  • Bubser M, Keseberg U, Notz PK, Schmidt WJ. Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol. 1992 Dec 8;229(1):75–82. [PubMed]
  • Burkhardt C, Kelly JP, Lim YH, Filley CM, Parker WD., Jr Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol. 1993 May;33(5):512–517. [PubMed]
  • Byczkowski JZ, Borysewicz R. The action of chlorpromazine and imipramine on rat brain mitochondria. Gen Pharmacol. 1979;10(5):369–372. [PubMed]
  • Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, Lipton SA. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci. 1992 Nov;12(11):4427–4436. [PubMed]
  • Danysz W, Essmann U, Bresink I, Wilke R. Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol Biochem Behav. 1994 May;48(1):111–118. [PubMed]
  • De Keyser J. Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol. 1991 Dec;14(6):562–565. [PubMed]
  • Egan MF, Hurd Y, Hyde TM, Weinberger DR, Wyatt RJ, Kleinman JE. Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic-induced dyskinesias. Synapse. 1994 Nov;18(3):178–189. [PubMed]
  • Favaron M, Manev H, Alho H, Bertolino M, Ferret B, Guidotti A, Costa E. Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7351–7355. [PubMed]
  • Gallagher CH, Koch JH, Mann DM. The effect of phenothiazine on the metabolism of liver mitochondria. Biochem Pharmacol. 1965 May;14(5):789–797. [PubMed]
  • Goff DC, Tsai G, Beal MF, Coyle JT. Tardive dyskinesia and substrates of energy metabolism in CSF. Am J Psychiatry. 1995 Dec;152(12):1730–1736. [PubMed]
  • Gunne LM, Andersson U, Bondesson U, Johansson P. Spontaneous chewing movements in rats during acute and chronic antipsychotic drug administration. Pharmacol Biochem Behav. 1986 Oct;25(4):897–901. [PubMed]
  • Imperato A, Di Chiara G. Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by trans-striatal dialysis. J Neurosci. 1985 Feb;5(2):297–306. [PubMed]
  • Jeste DV, Caligiuri MP. Tardive dyskinesia. Schizophr Bull. 1993;19(2):303–315. [PubMed]
  • Jeste DV, Lohr JB, Manley M. Study of neuropathologic changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats. Psychopharmacology (Berl). 1992;106(2):154–160. [PubMed]
  • Kornhuber J, Weller M, Schoppmeyer K, Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994;43:91–104. [PubMed]
  • Levin ED, See RE, South D. Effects of dopamine D1 and D2 receptor antagonists on oral activity in rats. Pharmacol Biochem Behav. 1989 Sep;34(1):43–48. [PubMed]
  • Lipton SA. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci. 1993 Dec;16(12):527–532. [PubMed]
  • Manev H, Costa E, Wroblewski JT, Guidotti A. Abusive stimulation of excitatory amino acid receptors: a strategy to limit neurotoxicity. FASEB J. 1990 Jul;4(10):2789–2797. [PubMed]
  • Marco LA, Joshi RS. A ketamine-induced rat model of tardive dyskinesia. Prog Neurobiol. 1992 Jun;38(6):571–600. [PubMed]
  • McGeer EG, McGeer PL. Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids. Nature. 1976 Oct 7;263(5577):517–519. [PubMed]
  • Meshul CK, Stallbaumer RK, Taylor B, Janowsky A. Haloperidol-induced morphological changes in striatum are associated with glutamate synapses. Brain Res. 1994 Jun 20;648(2):181–195. [PubMed]
  • Miller R, Chouinard G. Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia. Biol Psychiatry. 1993 Nov 15;34(10):713–738. [PubMed]
  • Mistry R, Wilke R, Challiss RA. Modulation of NMDA effects on agonist-stimulated phosphoinositide turnover by memantine in neonatal rat cerebral cortex. Br J Pharmacol. 1995 Feb;114(4):797–804. [PubMed]
  • Misztal M, Frankiewicz T, Parsons CG, Danysz W. Learning deficits induced by chronic intraventricular infusion of quinolinic acid--protection by MK-801 and memantine. Eur J Pharmacol. 1996 Jan 18;296(1):1–8. [PubMed]
  • Moghaddam B, Bunney BS. Depolarization inactivation of dopamine neurons: terminal release characteristics. Synapse. 1993 Jul;14(3):195–200. [PubMed]
  • Ossowska K. The role of excitatory amino acids in experimental models of Parkinson's disease. J Neural Transm Park Dis Dement Sect. 1994;8(1-2):39–71. [PubMed]
  • Parsons CG, Gruner R, Rozental J, Millar J, Lodge D. Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan). Neuropharmacology. 1993 Dec;32(12):1337–1350. [PubMed]
  • Rogawski MA. Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. Trends Pharmacol Sci. 1993 Sep;14(9):325–331. [PubMed]
  • Rosengarten H, Schweitzer JW, Friedhoff AJ. Induction of oral dyskinesias in naive rats by D1 stimulation. Life Sci. 1983 Dec 19;33(25):2479–2482. [PubMed]
  • Schneider E, Fischer PA, Clemens R, Balzereit F, Fünfgeld EW, Haase HJ. Wirkungen oraler Memantin-Gaben auf die Parkinson-Symptomatik. Ergebnisse einer placebo-kontrollierten Multicenter-Studie. Dtsch Med Wochenschr. 1984 Jun 22;109(25):987–990. [PubMed]
  • Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10771–10778. [PubMed]
  • Spanagel R, Eilbacher B, Wilke R. Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study. Eur J Pharmacol. 1994 Sep 1;262(1-2):21–26. [PubMed]
  • Waddington JL. Schizophrenia, affective psychoses, and other disorders treated with neuroleptic drugs: the enigma of tardive dyskinesia, its neurobiological determinants, and the conflict of paradigms. Int Rev Neurobiol. 1989;31:297–353. [PubMed]
  • Waddington JL, Cross AJ, Gamble SJ, Bourne RC. Spontaneous orofacial dyskinesia and dopaminergic function in rats after 6 months of neuroleptic treatment. Science. 1983 Apr 29;220(4596):530–532. [PubMed]
  • Wesemann W, Sontag KH, Maj J. Zur Pharmakodynamik und Pharmakokinetik des Memantin. Arzneimittelforschung. 1983;33(8):1122–1134. [PubMed]
  • Westerink BH, de Vries JB. On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals. Neurosci Lett. 1989 Apr 24;99(1-2):197–202. [PubMed]
  • Willetts J, Balster RL, Leander JD. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci. 1990 Oct;11(10):423–428. [PubMed]
  • Yamamoto BK, Cooperman MA. Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci. 1994 Jul;14(7):4159–4166. [PubMed]
Articles from British Journal of Pharmacology are provided here courtesy of
The British Pharmacological Society

PubMed articles by these authors