Changes in rat frontal cortex gene expression following chronic cocaine.
Alterations in gene expression caused by repeated cocaine administration have been implicated in the long-term behavioral aspects of cocaine abuse. The frontal cortex mediates reinforcement, sensory, associative, and executive functions and plays an important role in the mesocortical dopamine reinforcement system. Repeated cocaine administration causes changes in frontal cortex gene expression that may lead to changes in the behaviors subserved by this brain region. Rats treated non-contingently with a binge model of cocaine (45 mg/kg/day, i.p.) for 14 days were screened for changes in relative mRNA abundance in the frontal cortex by cDNA hybridization arrays. To confirm changes, immunoreactive protein was measured (via protein-specific immunoblots) in a second group of identically-treated animals. Protein levels of protein tyrosine kinase 2 (PYK2), activity-regulated cytoskeletal protein (ARC), as well as an antigen related to nerve growth factor I-B (NGFI-B-RA) were shown to be significantly induced after cocaine administration. Levels of NGFI-B mRNA were confirmed by real-time RT-PCR to be increased with cocaine administration. These observations are similar to previously reported cocaine-responsive changes in gene expression but novel to the frontal cortex. This study also validates the use of hybridization arrays for screening of neuronal gene expression changes and the utility of relative protein quantification as a post-hoc confirmation tool.
Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA. freemanw@ohsu.edu
Willard M
WM
Freeman
Karen
K
Brebner
Wendy J
WJ
Lynch
Kruti M
KM
Patel
Daniel J
DJ
Robertson
David C S
DC
Roberts
Kent E
KE
Vrana
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004334:Drug Administration Schedule; D051418:Focal Adhesion Kinase 2; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D015151:Immunoblotting; D017403:In Situ Hybridization; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C092069:activity regulated cytoskeletal-associated protein; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D003042:Cocaine