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 increases in c-fos mRNA expression in the same region. Our recent studies demonstrate that a vast majority of haloperidol-sensitive NT/N mRNA expressing cells in the dorsolateral striatum coexpress c-fos mRNA. These data suggest that the transcription factor, Fos, may participate in NT/N gene induction by neuroleptics. Present studies investigated this possibility using an antisense c-fos oligodeoxynucleotide (which has been shown to block the expression of Fos protein in vivo) or its sense sequence oligomer injected into opposite caudate-putamen of awake, freely moving rats. Eight hours following the injection of the oligomers, the animals were challenged with a systemic injection of haloperidol (1 mg/kg) and were sacrificed 1 h later. Examination of NT/N mRNA by in situ hybridization histochemistry revealed approximately 50% attenuation in the NT/N mRNA expression in the dorsolateral striatum injected with the antisense oligomer compared to the contralateral side which received the sense oligomer. On the other hand, expression of proenkephalin mRNA in the dorsolateral striatal neurons or NT/N mRNA in the nucleus accumbens shell was not altered following the c-fos antisense oligomer injection. These data demonstrate a specific role of Fos in the regulation of the neurotensin/neuromedin N gene in the rat dorsolateral striatal neurons by acute haloperidol treatment. (C) 1994 Academic Press, Inc.