COCAINE BINGES DIFFERENTIALLY ALTER STRIATAL PREPRODYNORPHIN AND ZIF 268 MESSENGER-RNAS/

Several studies have demonstrated that cocaine increases preprodynorph in, c-fos, and zif/268 mRNAs in rat dorsal striatum. Multiple, closely spaced exposures to cocaine appear to elicit the greatest increases i n dynorphin. However, the response of preproenkephalin, c-fos and zif/ 268 mRNAs to such a dosing regimen is unknown. Therefore, we used a 'b inge' paradigm to evaluate changes in mRNA for preprodynorphin, prepro enkephalin, c-fos and 2if/268. Male Wistar rats received three hourly i.p. injections of saline or 10 or 20 mg/kg cocaine for 1, 5, or 10 da ys. Although cocaine-induced locomotor and stereotypical behaviors wer e significantly increased as compared to saline on days 1, 5 and 10, t hese behaviors were significantly less on day 10 than on days 1 and 5. One hour after the last injection on days 1, 5, or 10, the rats were anesthetized and decapitated for quantitative in situ hybridization hi stochemistry. C-fos mRNA was undetectable in all treatment groups wher eas zif/268 mRNA in the dorsal striatum was increased in a dose-depend ent manner (20 mg/kg > 10 mg/kg) but the intensity of hybridization si gnal decreased over time (1 day much greater than 5 days > 10 days) as compared to that in saline-treated controls. In contrast, 10 mg/kg co caine binges caused an increase in preprodynorphin, but not preproenke phalin, mRNA in the dorsal, but not ventral, striatum in a time-depend ent manner (day 10 much greater than day 5 > day 1) whereas 20 mg/kg c ocaine binges caused an increase in striatal preprodynorphin that was greater on day 1 and day 5 than on day 10. These data indicate that (1 ) c-fos, zif/268 and preprodynorphin mRNAs are differentially regulate d in dorsal striatum, (2) behavioral tolerance results from chronic bi nges with 10 and 20 mg/kg cocaine and (3) the preprodynorphin genomic response exhibits tolerance to chronic high dose, but not low dose, co caine binges.