Persistent reduction of immediate early gene mRNA in rat forebrain following single or multiple doses of cocaine.
Stimulus-induced expression of immediate early genes (IEGs) is believed to be involved in the transduction of extracellular stimuli into prolonged modifications of cellular function. Previous studies have demonstrated that the IEGs NGFI-A (zif268) and c-fos are each rapidly induced in the caudate putamen (CP) by treatment with the indirect dopamine agonist cocaine. The short-term course of this induction has been well studied. However, the consequences of cocaine use are not limited to immediate pharmacological effects. Withdrawal, especially from prolonged or repeated use, can produce extended physiological and behavioral changes. At the cellular level, these longer-term effects may be mediated by or reflected in changes in the expression of IEGs. For this reason, we have investigated long-term perturbations in IEG expression during withdrawal from intravenously (IV) or intraperitoneally (IP) administered cocaine. Levels of NGFI-A and c-fos were measured in the CP of rats by Northern blot analysis, which confirmed that cocaine-induced increases of NGFI-A and c-fos mRNA lasts for several hours after drug administration. Immediately following this induction, however, there is a prolonged period during which a marked reduction in the relative amount of mRNA for both NGFI-A and c-fos is observed in cocaine-treated animals when compared to matched, vehicle-treated controls. This repression persisted for several hours after a single injection and as long as several days following multiple injections, strongly suggesting a cumulative effect for repeated exposures.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Psychiatry, Harvard Medical School, Belmont, MA.
D J
DJ
Ennulat
S m
Sm
Babb
B M
BM
Cohen
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004334:Drug Administration Schedule; D051766:Early Growth Response Protein 1; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D017874:Immediate-Early Proteins; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D003042:Cocaine