HALOPERIDOL-INDUCED FOS EXPRESSION IN STRIATUM IS DEPENDENT UPON TRANSCRIPTION FACTOR CYCLIC-AMP RESPONSE ELEMENT-BINDING PROTEIN

Haloperidol has been shown to induce rapid and transient expression of c-fos messenger RNA and Fos protein in striatal neurons via dopamine D-2 receptors. Regulation of the c-fos gene by cyclic AMP and Ca2+ has been shown to be dependent on a DNA regulatory element within its pro moter that binds the constitutively expressed transcription factor cyc lic AMP response element binding protein. Cyclic AMP response element binding protein binds to an oligonucleotide containing the calcium/cyc lic AMP response element of the c-fos promoter sequence in striatal ce ll extracts; the amount of binding is not regulated by haloperidol tre atment. We have previously shown that haloperidol induces cyclic AMP r esponse element binding protein phosphorylation in the striatum. Here we show by intrastriatal injection of antisense oligonucleotides that haloperidol-induced Fos expression is dependent on cyclic AMP response element binding protein. Intrastriatal injections of phosphorothioate oligonucleotides, in antisense orientation to cyclic AMP response ele ment binding protein messenger RNA, reduce levels of cyclic AMP respon se element binding protein and completely prevent haloperidol-mediated induction of Fos. Oligonucleotides in sense orientation have no such effect. We observed a markedly different time course of the Fos protei n inhibition by cyclic AMP response element binding protein antisense oligonucleotides compared to c-fos antisense oligonucleotides. This mo st likely reflects the different half-lives of c-fos and cyclic AMP re sponse element binding protein messenger RNA and proteins. Neither cyc lic AMP response element binding protein nor c-fos antisense oligonucl eotide injection reduced c-Jun immunostaining in the striatum. We conc lude that haloperidol induces Fos via transcription factor cyclic AMP response element binding protein.