Coordinate suppression of striatal ngfi-a and c-fos produces locomotor asymmetry and up-regulation of IEGs in the globus pallidus.
We have studied the effects of inhibition of c-Fos and NGFI-A expression by intrastriatal infusion of end-capped antisense oligodeoxynucleotides to determine if their coordinate expression is conferred independently or through regulatory influences exerted between these two proteins. The previously reported locomotor bias that has been associated with unilateral c-Fos suppression was also investigated in animals receiving antisense oligodeoxynucleotides targeted to ngfi-a to determine if the behavior is specific to alterations in c-Fos expression, or if its cause may be a generalized imbalance of striatal IEGs. We show here that while unilateral suppression of c-Fos has negligible effects on NGFI-A, oligodeoxynucleotides targeted to ngfi-a markedly inhibit both NGFI-A and c-Fos expression. Animals with extensive unilateral reduction of either or both proteins demonstrated robust ipsiversive rotation when challenged with D-amphetamine. Infusions of random oligodeoxynucleotides produced neither a reduction in c-Fos or NGFI-A expression, nor a significant rotational bias following D-amphetamine challenge. Surprisingly, animals with extensive striatal IEG suppression were found to have marked up-regulation of c-Fos and NGFI-A in the ipsilateral globus pallidus, a finding which may ultimately shed light on the mechanism of antisense-induced rotational behavior.
Hebb
M O
MO
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Robertson
H A
HA
D000818:Animals; D001479:Basal Ganglia / Q000502:physiology; D001483:Base Sequence; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003913:Dextroamphetamine / Q000494:pharmacology; D051766:Early Growth Response Protein 1; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D008297:Male; D008959:Models, Neurological; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D003913:Dextroamphetamine