Cocaine differentially regulates activator protein-1 mRNA levels and DNA-binding complexes in the rat striatum and cerebellum.
Cocaine is a psychomotor stimulant that exerts many of its behavioral and physiological effects through alteration of catecholamine reuptake systems. One early cellular response to cocaine administration is a brain region-specific alteration in the transcriptional pattern of immediate early genes belonging to the Fos/Jun family of nucleotide sequence-specific [activator protein-1 (AP-1)] DNA-binding proteins. The work described here compares cocaine-induced transcriptional regulation of immediate early gene mRNA levels, as well as AP-1 DNA-binding activity, within the striatum and cerebellum. In the striatum, acute cocaine administration increases cellular levels of c-fos and jun-B mRNA, whereas transcriptional effects in the cerebellum are limited to c-fos mRNA. After chronic cocaine treatment a desensitization of c-fos mRNA induction is observed in the striatum, with sensitization of the same transcriptional effect occurring in the cerebellum. Pharmacological studies further reveal that the dopamine D1, dopamine D2, gamma-aminobutyric acid type B, and N-methyl-D-aspartate receptor systems mediate the effects of cocaine on cerebellar neurons, whereas striatal effects are modulated through D1 and N-methyl-D-aspartate receptors. Gel retention analysis using antibodies to the various Fos and Jun proteins was used to characterize cocaine-dependent alterations in the composition of striatal and cerebellar AP-1 DNA-binding complexes. In striatum, cocaine increases the relative levels of c-Fos, Fos-B, Jun-B, and Jun-D proteins that bind the AP-1 DNA sequence element, whereas in the cerebellum only c-Fos and Jun-D binding activities are increased. These data suggest two possible neuroanatomical sites where tolerance and sensitization to cocaine can be examined at the genomic level.
Vollum Institute, Oregon Health Sciences University, Portland 97201.
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P
Couceyro
K M
KM
Pollock
K
K
Drews
J
J
Douglass
D000818:Animals; D001483:Base Sequence; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016762:Genes, fos; D016758:Genes, jun; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000235:genetics*
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003042:Cocaine