Expression of glutamic acid decarboxylase mRNA 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 haloperidol for 8 and 12 months but not 28 days. We have examined the effects of these long-term haloperidol treatments on the levels of mRNA encoding glutamic acid decarboxylase (GAD, M(r) 67,000), the rate-limiting enzyme of GABA synthesis, in the striatum and pallidum of adult rats. Despite the differences in behavior, GAD67 mRNA was increased in the striatum and entopeduncular nucleus (internal pallidum) after both 28 days and 8 months of haloperidol administration. In contrast, only long-term haloperidol treatments (8 and 12 months) decreased GAD67 mRNA in globus pallidus (external pallidum). This effect contrasted with the increased level of GAD67 mRNA we have previously observed in the globus pallidus after short-term haloperidol treatment (3-14 days), a regimen that induces catalepsy. Together with data indicating a loss of GAD activity in target areas of the globus pallidus in humans with tardive dyskinesia, the results suggest that decreased GABAergic transmission in the projection neurons of the external pallidum may play a critical role in the motor side effects associated with long-term neuroleptic therapy.
Delfs
J M
JM
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Ellison
G D
GD
Mercugliano
M
M
Chesselet
M F
MF
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005917:Globus Pallidus / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006220:Haloperidol / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000235:genetics
D004745:Enkephalins; D012333:RNA, Messenger; D013373:Substance P; D005968:Glutamate Decarboxylase; D006220:Haloperidol