C-FOS MEDIATES ANTIPSYCHOTIC-INDUCED NEUROTENSIN GENE-EXPRESSION IN THE RODENT STRIATUM

The ubiquitous inducibility of the immediate-early gene c-fos in the c entral nervous system has led to the search for downstream genes which are regulated by its product, Fos. Recent evidence suggests that c-fo s induction by a single injection of the classical antipsychotic halop eridol may contribute to the subsequent increase in neurotensin gene e xpression in the rodent striatum. Consistent with this proposal, in th e present study haloperidol-induced Fos-like immunoreactivity and neur otensin/neuromedin N messenger RNA were found to be expressed by the s ame population of striatal neurons. Moreover, inhibition of haloperido l-induced c-fos expression by intrastriatal injection of antisense pho sphorothioate oligodeoxynucleotides complimentary either to bases 109- 126 or 127-144 of c-fos attenuated the subsequent increase in neuroten sin/neuromedin N messenger RNA. However, injection of a sense phosphor othioate oligodeoxynucleotide corresponding to bases 127-144 of c-fos did not reduce haloperidol-induced c-fos or neurotensin/neuromedin N e xpression. Furthermore, constitutive expression of Jun-like immunoreac tivity in the striatum was not reduced by either the sense or antisens e phosphorothioate oligodeoxynucleotides. Similarly, the sense and ant isense phosphorothioate oligodeoxynucleotide failed to reduce proenkep halin messenger RNA, which is located in the same striatal neurons tha t express haloperidol-induced neurotensin/neuromedin N messenger RNA. Lastly, haloperidol-induced increases in nerve growth factor I-A-, Jun B- and FosB-like immunoreactivity and fosB messenger RNA were not decr eased by intrastriatal injection of either the sense or antisense phos phorothioate oligodeoxynucleotides. These results indicate that the an tisense phosphorothioate oligodeoxynucleotides attenuated haloperidol- induced neurotensin/neuromedin N expression by selectively reducing c- fos expression and emphasize the potential importance of immediate-ear ly gene induction in the mechanism of action of this antipsychotic dru g.