INHIBITION BY MEMANTINE OF THE DEVELOPMENT OF PERSISTENT ORAL DYSKINESIAS INDUCED BY LONG-TERM HALOPERIDOL TREATMENT OF RATS

1 Tardive dyskinesia (TD) is a serious side-effect of long-term treatm ent with neuroleptics. To investigate if neuroleptic-induced excessive stimulation of striatal glutamate receptors may underlie TD developme nt, the effect of the NMDA antagonist, memantine (1-amino-3,5-dimethyl adamantane), was studied in a rat model of TD. 2 In an acute experimen t, six groups of rats were treated daily for 1 week with either vehicl e 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 sa line i.p. In a subsequent long-term experiment lasting 20 weeks, the s ame treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg(-1) every 4 weeks) and control rats received s esame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long-term t reatment. 3 In the acute experiment, haloperidol decreased motor activ ity and memantine increased moving and tended to attenuate the immobil ity induced by haloperidol. Memantine also enhanced the haloperidol-in duced increase in the putative TD-analogue vacuous chewing movements ( VCM). 4 In the long-term experiment, the most marked effect of haloper idol was a gradual increase in VCM and the increase persisted signific antly for 12 weeks after cessation of treatment. Memantine dose-depend ently increased VCM and moving during long-term treatment. However, on ly one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol a lone, rats co-treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The b lood levels of drugs were within the therapeutic range achieved in hum an 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.