C-FOS ANTISENSE OLIGONUCLEOTIDE SPECIFICALLY ATTENUATES HALOPERIDOL-INDUCED INCREASES IN NEUROTENSIN NEUROMEDIN-N MESSENGER-RNA EXPRESSION IN RAT DORSAL STRIATUM

Acute administration of neuroleptic drugs such as haloperidol robustly increases transcription of the gene encoding the neuroactive peptide, neurotensin, in the dorsolateral striatum of the rat. This induction of neurotensin/neuromedin (NT/N) mRNA by haloperidol is preceded by in creases in c-fos mRNA expression in the same region. Our recent studie s demonstrate that a vast majority of haloperidol-sensitive NT/N mRNA expressing cells in the dorsolateral striatum coexpress c-fos mRNA. Th ese data suggest that the transcription factor, Fos, may participate i n NT/N gene induction by neuroleptics. Present studies investigated th is possibility using an antisense c-fos oligodeoxynucleotide (which ha s been shown to block the expression of Fos protein in vivo) or its se nse sequence oligomer injected into opposite caudate-putamen of awake, freely moving rats. Eight hours following the injection of the oligom ers, the animals were challenged with a systemic injection of haloperi dol (1 mg/kg) and were sacrificed 1 h later. Examination of NT/N mRNA by in situ hybridization histochemistry revealed approximately 50% att enuation in the NT/N mRNA expression in the dorsolateral striatum inje cted with the antisense oligomer compared to the contralateral side wh ich received the sense oligomer. On the other hand, expression of proe nkephalin mRNA in the dorsolateral striatal neurons or NT/N mRNA in th e nucleus accumbens shell was not altered following the c-fos antisens e oligomer injection. These data demonstrate a specific role of Fos in the regulation of the neurotensin/neuromedin N gene in the rat dorsol ateral striatal neurons by acute haloperidol treatment. (C) 1994 Acade mic Press, Inc.