Postnatal age defines specificity of immediate early gene induction by cocaine in developing rat brain.
Clinical and animal data suggest that exposure of developing brain to cocaine has adverse consequences. One candidate mechanism for such effects is drug regulation of gene expression. In adult rats, cocaine induces expression of nuclear immediate early genes with specific spatial and temporal patterns. The products of such genes (e.g., c-Fos, c-Jun, and Zif/268) subserve the coupling of cell surface receptor stimulation to transcriptional regulation. Thus, activation of immediate early gene expression in developing brain by cocaine could alter programs of neural gene expression and, thereby, neuronal phenotype and function. We report that, during rat brain development, cocaine produced brain region-specific and developmental age-specific induction of c-fos, c-jun, and zif/268 mRNAs. At each age studied (P8, P15, P28, and adults), we found that acute cocaine administration resulted in a unique cell-specific pattern of c-fos mRNA induction and c-Fos protein expression in striatum. We also observed cocaine-induced activation of AP-1 DNA binding activity in striatal extracts prepared at these different ages, suggesting that the observed induction of c-fos and c-jun may have biological consequences for the developing brain. These findings suggest a mechanism by which cocaine could alter patterns of gene expression during critical developmental periods with differential regional, temporal, and cellular vulnerabilities and, therefore, consequences for developing brain.
Kosofsky
B E
BE
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Boston 02114.
Genova
L M
LM
Hyman
S E
SE
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001483:Base Sequence; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D017072:Neostriatum / Q000033:anatomy & histology / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D003042:Cocaine