Long-lasting dysregulation of gene expression in corticostriatal circuits after repeated cocaine treatment in adult rats: effects on zif 268 and homer 1a.
Human imaging studies show that psychostimulants such as cocaine produce functional changes in several areas of cortex and striatum. These may reflect neuronal changes related to addiction. We employed gene markers (zif 268 and homer 1a) that offer a high anatomical resolution to map cocaine-induced changes in 22 cortical areas and 23 functionally related striatal sectors, in order to determine the corticostriatal circuits altered by repeated cocaine exposure (25 mg/kg, 5 days). Effects were investigated 1 day and 21 days after repeated treatment to assess their longevity. Repeated cocaine treatment increased basal expression of zif 268 predominantly in sensorimotor areas of the cortex. This effect endured for 3 weeks in some areas. These changes were accompanied by attenuated gene induction by a cocaine challenge. In the insular cortex, the cocaine challenge produced a decrease in zif 268 expression after the 21-day, but not 1-day, withdrawal period. In the striatum, cocaine also affected mostly sensorimotor sectors. Repeated cocaine resulted in blunted inducibility of both zif 268 and homer 1a, changes that were still very robust 3 weeks later. Thus, our findings demonstrate that cocaine produces robust and long-lasting changes in gene regulation predominantly in sensorimotor corticostriatal circuits. These neuronal changes were associated with behavioral stereotypies, which are thought to reflect dysfunction in sensorimotor corticostriatal circuits. Future studies will have to elucidate the role of such neuronal changes in psychostimulant addiction.
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, North Chicago, IL 60064, USA.
Cagri T
CT
Unal
Joel A
JA
Beverley
Ingo
I
Willuhn
Heinz
H
Steiner
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D000072233:Homer Scaffolding Proteins; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D000072233:Homer Scaffolding Proteins; D003042:Cocaine