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.
Hooper
M L
ML
Department of Pharmacology, Faculty of Medicine, Dalhousie University, Canada.
Chiasson
B J
BJ
Robertson
H A
HA
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000235:genetics*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects
D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D000661:Amphetamine