ORAL DYSKINESIAS AND STRIATAL LESIONS IN RATS AFTER LONG-TERM CO-TREATMENT WITH HALOPERIDOL AND 3-NITROPROPIONIC ACID

The pathophysiologic basis of tardive dyskinesia remains unclear. It h as been proposed that tardive dyskinesia may be a result of excitotoxi c neurodegeneration in the striatum caused by a neuroleptic-induced in crease in striatal glutamate release and impaired energy metabolism To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four wee ks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitrop ropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. C ontrol rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue t o human tardive dyskinesia, were recorded during and after drug treatm ent. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropio nic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, Vacuous chewing movements were more pronounced an d appeased earlier in rats treated with 3-nitropropionic acid+haloperi dol. After drug withdrawal, increases in vacuous chewing movements per sisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid +haloperidol group and for four weeks in the 3-nitropropionic acid alo ne group. Brains from each group were analysed for histopathological a lterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acidhaloperidol-treated rats. Nerve cell depletion and astrogliosis were p rominent histopathologic features. There was selective neuronal sparin g of both large- and medium-sized aspiny striatal neurons. These resul ts suggest that mild mitochondrial impairment in combination with neur oleptics results in striatal excitotoxic neurodegeneration which may u nderlie the development of persistent vacuous chewing movements in rat s and possibly irreversible tardive dyskinesia in humans. (C) 1998 IBR O. Published by Elsevier Science Ltd.