Guerriero Rejean M, Rajadhyaksha Anjali, Crozatier Claire, Giros Bruno, Nosten-Bertrand Marika, Kosofsky Barry E
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital-East, Charlestown, MA, USA.
Dev Neurosci. 2005 Mar-Aug;27(2-4):235-48. doi: 10.1159/000085997.
Neuroadaptations occurring in the mesolimbic dopamine pathway following recurrent exposure to drugs of abuse have been correlated with a behavioral phenomenon known as behavioral sensitization. We have developed an animal model of prenatal cocaine exposure and, using a postnatal sensitization protocol, have examined the subsequent sensitivity of offspring to cocaine. Pregnant Swiss Webster dams were injected twice daily from embryonic day 8 to 17, inclusive, with cocaine (COC40: administered cocaine HCl at a dose of 40 mg/kg/day, and COC20: administered cocaine HCl at a dose of 20 mg/kg/day), or saline (SAL). The SPF40 group (saline pair-fed), a nutritional control group, was 'pair-fed' with COC40 dams. Activity was recorded for 30 min during a 3-day saline habituation, a 14-day 'initiation' phase, when animals received cocaine (15 mg/kg) or saline every other day, and following a 21-day 'withdrawal' period when all mice were challenged with cocaine. COC40 offspring, as compared with SAL controls, did not habituate to a novel environment, demonstrated increased cocaine-induced stereotypy on Coc 1 (first cocaine injection), and blunted locomotor sensitization on challenge as measured by the percentage of each animal's baseline locomotion. Tissue samples of the nucleus accumbens (NAc) and striatum (Str) of all four prenatal treatment groups were examined to determine whether alterations in the transcription factor CREB or glutamate receptor subunit, GluR1, induced by prenatal cocaine treatment may have contributed to the altered behavioral responses. Immunoblot quantitation revealed significantly increased constitutive CREB expression in the NAc and Str of COC40 mice as compared with SAL controls. Such alterations in constitutive CREB levels may contribute to some of the behavioral differences reported in adult mice exposed to cocaine in utero.
反复接触滥用药物后，中脑边缘多巴胺通路中出现的神经适应性变化与一种被称为行为敏化的行为现象相关。我们建立了一个产前可卡因暴露的动物模型，并采用产后敏化方案，研究了后代对可卡因的后续敏感性。怀孕的瑞士韦伯斯特母鼠从胚胎第8天到第17天（含第17天）每天注射两次，分别注射可卡因（COC40：以40 mg/kg/天的剂量注射盐酸可卡因；COC20：以20 mg/kg/天的剂量注射盐酸可卡因）或生理盐水（SAL）。营养对照组SPF40组（生理盐水配对喂养组）与COC40母鼠进行“配对喂养”。在为期3天的生理盐水适应期、为期14天的“起始”阶段（在此期间动物每隔一天接受一次可卡因（15 mg/kg）或生理盐水注射）以及为期21天的“戒断”期（在此期间所有小鼠都接受可卡因激发）内，记录动物活动30分钟。与SAL对照组相比，COC40后代对新环境不产生习惯化，在首次注射可卡因（Coc 1）时表现出可卡因诱导的刻板行为增加，并且在激发时运动敏化减弱，通过每只动物基线运动的百分比来衡量。对所有四个产前治疗组的伏隔核（NAc）和纹状体（Str）组织样本进行检查，以确定产前可卡因治疗诱导的转录因子CREB或谷氨酸受体亚基GluR1的改变是否可能导致行为反应改变。免疫印迹定量分析显示，与SAL对照组相比，COC40小鼠的NAc和Str中组成型CREB表达显著增加。组成型CREB水平的这种改变可能导致了成年期子宫内接触可卡因的小鼠所报道的一些行为差异。
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