INFUSION INTO THE BRAIN OF AN ANTISENSE OLIGONUCLEOTIDE TO THE IMMEDIATE-EARLY GENE C-FOS SUPPRESSES PRODUCTION OF FOS AND PRODUCES A BEHAVIORAL-EFFECT

While many studies have examined the numerous physiological and pharmacological factors which can induce the expression of c-fos and other immediate-early genes, few have examined the physiological/biochemical consequences of altering their expression pattern. Using antisense oligonucleotides to c-fos, we demonstrate that D-amphetamine-induced c-fos expression can be attenuated in specific brain regions in vivo. This unilateral attenuation of c-fos expression in D-amphetamine-stimulated animals results in a directed rotational behavior. We show that animals rotate only when they express a difference in Fos-like immunoreactivity between hemispheres. The attenuation of Fos-like immunoreactivity by the antisense oligonucleotides appears to be dependent on the c-fos messenger RNA site that these antisense oligonucleotides target and the degree of chemical protection of the oligonucleotide against degradation. The attenuation of Fos-like immunoreactivity and the increase in unilaterally directed rotation are both time- and dose-dependent. These results demonstrate that manipulating immediate-early gene expression by the direct infusion of antisense oligonucleotides in specific brain regions can have behavioral consequences.