Daunais J B, McGinty J F
Department of Anatomy and Cell Biology, East Carolina University School of Medicine, Greenville, NC 27858-4354, USA.
Brain Res Mol Brain Res. 1995 Apr;29(2):201-10. doi: 10.1016/0169-328x(94)00246-b.
Several studies have demonstrated that cocaine increases preprodynorphin, c-fos, and zif/268 mRNAs in rat dorsal striatum. Multiple, closely spaced exposures to cocaine appear to elicit the greatest increases in dynorphin. However, the response of preproenkephalin, c-fos and zif/268 mRNAs to such a dosing regimen is unknown. Therefore, we used a 'binge' paradigm to evaluate changes in mRNA for preprodynorphin, preproenkephalin, c-fos and zif/268. Male Wistar rats received three hourly i.p. injections of saline or 10 or 20 mg/kg cocaine for 1, 5, or 10 days. Although cocaine-induced locomotor and stereotypical behaviors were significantly increased as compared to saline on days 1, 5 and 10, these 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 histochemistry. C-fos mRNA was undetectable in all treatment groups whereas zif/268 mRNA in the dorsal striatum was increased in a dose-dependent manner (20 mg/kg > 10 mg/kg) but the intensity of hybridization signal decreased over time (1 day >> 5 days > 10 days) as compared to that in saline-treated controls. In contrast, 10 mg/kg cocaine binges caused an increase in preprodynorphin, but not preproenkephalin, mRNA in the dorsal, but not ventral, striatum in a time-dependent manner (day 10 >> day 5 > day 1) whereas 20 mg/kg cocaine 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 regulated in dorsal striatum, (2) behavioral tolerance results from chronic binges with 10 and 20 mg/kg cocaine and (3) the preprodynorphin genomic response exhibits tolerance to chronic high dose, but not low dose, cocaine binges.
多项研究表明，可卡因可增加大鼠背侧纹状体中前强啡肽原、c-fos和zif/268的信使核糖核酸（mRNA）水平。多次、间隔紧密地接触可卡因似乎能使强啡肽的增加最为显著。然而，前脑啡肽原、c-fos和zif/268的mRNA对这种给药方案的反应尚不清楚。因此，我们采用“暴饮暴食”模式来评估前强啡肽原、前脑啡肽原、c-fos和zif/268的mRNA变化。雄性Wistar大鼠连续1、5或10天，每小时经腹腔注射生理盐水或10或20毫克/千克可卡因。尽管与生理盐水相比，在第1、5和10天，可卡因诱导的运动和刻板行为显著增加，但在第10天这些行为比第1天和第5天显著减少。在第1、5或10天最后一次注射后1小时，将大鼠麻醉并断头，用于定量原位杂交组织化学分析。在所有治疗组中均未检测到c-fos mRNA，而背侧纹状体中的zif/268 mRNA以剂量依赖性方式增加（20毫克/千克>10毫克/千克），但与生理盐水处理的对照组相比，杂交信号强度随时间下降（1天>>5天>10天）。相反，10毫克/千克可卡因“暴饮暴食”导致背侧而非腹侧纹状体中的前强啡肽原mRNA以时间依赖性方式增加（第10天>>第5天>第1天），但前脑啡肽原mRNA未增加；而20毫克/千克可卡因“暴饮暴食”导致纹状体前强啡肽原增加，在第1天和第5天比第10天更明显。这些数据表明：（1）c-fos、zif/268和前强啡肽原mRNA在背侧纹状体中受到不同调节；（2）行为耐受性源于10和20毫克/千克可卡因的慢性“暴饮暴食”；（3）前强啡肽原基因反应对慢性高剂量而非低剂量可卡因“暴饮暴食”表现出耐受性。
