Jm. Delfs et al., EXPRESSION OF GLUTAMIC-ACID DECARBOXYLASE MESSENGER-RNA IN STRIATUM AND PALLIDUM IN AN ANIMAL-MODEL OF TARDIVE-DYSKINESIA, Experimental neurology, 133(2), 1995, pp. 175-188
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.