EXPRESSION OF GLUTAMIC-ACID DECARBOXYLASE MESSENGER-RNA IN STRIATUM AND PALLIDUM IN AN ANIMAL-MODEL OF TARDIVE-DYSKINESIA

Long-term administration of neuroleptics can induce tardive dyskinesia in humans. Oral movements with the same distinctive form observed in humans with tardive dyskinesia are observed in rats treated with halop eridol for 8 and 12 months but not 28 days. We have examined the effec ts of these long-term haloperidol treatments on the levels of mRNA enc oding glutamic acid decarboxylase (GAD, M(r), 67,000), the rate-limiti ng enzyme of GABA synthesis, in the striatum and pallidum of adult rat s. Despite the differences in behavior, GAD67 mRNA was increased in th e striatum and entopeduncular nucleus (internal pallidum) after both 2 8 days and 8 months of haloperidol administration. In contrast, only l ong-term haloperidol treatments (8 and 12 months) decreased GAD67 mRNA in globus pallidus (external pallidum). This effect contrasted with t he increased level of GAD67 mRNA we have previously observed in the gl obus pallidus after short-term haloperidol treatment (3-14 days), a re gimen that induces catalepsy. Together with data indicating a loss of GAD activity in target areas of the globus pallidus in humans with tar dive dyskinesia, the results suggest that decreased GABAergic transmis sion in the projection neurons of the external pallidum may play a cri tical role in the motor side effects associated with long-term neurole ptic therapy. (C) 1995 Academic Press, Inc.