Effects of morphine on immediate-early gene expression in the striatum of C57BL/6J and DBA/2J mice.

摘要

Background: Immediate early gene (IEG) induction elicited by drugs of abuse may contribute to development of plastic changes in the brain responsible for drug-induced behavioral changes leading to addiction. The aim of the present study was to characterize the changes in IEG expression in the striatum and nucleus accumbens produced by an acute or chronic administration of morphine. Methods: In order to search for a possible relationship between morphine-induced IEG expression and behavior, the experiment was performed on two inbred strains of mice, C57BL/6J and DBA/2J, which differ markedly in their sensitivity to the rewarding and lo- comotor stimulatory actions of opiates. Gene expression was assessed using RT-PCR and DNA microarrays. Results: The experiments demonstrated a prolonged or a delayed up-regulation of 14 IEG in the striatum at 4 h after morphine ad- ministration. Among them, a cluster of 8 genes, including 6 inducible transcription factors (c-fos, fra-2, junB, zif268 (egr1), egr2, NGFI-B) and 2 effector IEG (arc and mkp1) seemed to be regulated in concert in response to morphine. This group of genes was in- duced to a greater degree after chronic than acute morphine administration selectively in C57BL/6J mice and the difference bore ap- parently no relationship to opiate-produced locomotor activation. The strain-selective regulation was also demonstrated for cyclin L2 and tPA after an acute morphine injection. Conclusions: Our data indicate that morphine up-regulates many IEG in the mouse striatum at a strikingly delayed time-point and that these changes are genotype-dependent. They also suggest inter-strain differences in the development of striatal neuroadapta- tions to chronic morphine treatment.