Prenatal stress in rats : effects of cytogenesis, cocaine-induced place preference and dopamine

本研究探讨了出生前应激对子代大鼠脑室下区细胞发生的影响，这可能与奖励可卡因的效果改变有关。在5个胚胎期(E13至E17)，怀孕母鼠在Bolman笼子中被限制45min，每天三次，暴露于两道明亮的(150W)光下。为了进行细胞增殖研究，在E13、E15和E17天的每次应激后，DAMS被注射细胞增殖标记物5-溴-2‘脱氧尿苷(BrdU；50 mg/kg，ip)。于出生后第7天或第10天灌流幼鼠，分别在海马区颗粒下带和脑室下带计数BrdU阳性细胞。为探讨可卡因对仔鼠的奖赏效应，对10周龄仔鼠进行可卡因(0、2.5、5.0、10.0 mg/kg，ip)训练。建立地点偏好。此外，应用体内微渗析和高效液相色谱检测了可卡因对伏隔核胞外多巴胺浓度的影响。结果显示：(1)孕期应激子代大鼠的BrdU阳性细胞不仅在颗粒下区而且在脑室下区显著减少；(2)条件性位置偏爱实验显示可卡因的奖赏效应高于对照子代。但是，产前应激并不影响可卡因增加的伏核细胞外多巴胺。结果表明，产前应激，特别是在妊娠后期施加的应激，可能导致胎儿脑室下区细胞增殖减少，并使可卡因对有回报的可卡因过敏。后者的改变似乎不是由于伏隔区多巴胺对可卡因的过度反应。

The present study examined the effects of prenatal stress on the cytogenesis in the subventricular zone that may implicate in the altered effectiveness of rewarding cocaine in the offspring rats.During five embryonic days (E13 to E17), pregnant dams were restrained for 45 min, three times a day, in the Bolman cages exposed to two bright (150w) lights. For cell-proliferation study, dams were injected with a cell-proliferation marker 5-bromo-2' deoxyuridine (BrdU ; 50mg/kg, i.p.), following each stress session on days of E13, E15, and E17. Pups were then perfused on postnatal day 7 or 10 and BrdU-positive cells were counted in the subgranular zone of the hippocamus and the subventricular zone, respectively. To investigate rewarding effectiveness of cocaine in the offspring rats, ten-week-old offsprings were trained with cocaine (0, 2.5, 5.0, 10.0 mg/kg, i.p.) to establish place preference. Additionally, cocaine-enhanced extracellular dopamine concentration in the nucleus accumbens, was examined by using in-vivo microdialysis and high-performance liquid chromatography.The prenatally stressed offsprings showed (1) remarkably fewer BrdU positive cells not only in the subgranular zone but also in the subventricular zone and (2) Higher rewarding effectiveness of cocaine revealed in conditioned place preference test than that in control offsprings. But, prenatal stress did not affect the cocaine-increased extracellular dopamine in the nucleus accumbens.The results indicate that prenatal stress, particularly applied during the later period of pregnancy, may lead to a reduction in cell proliferation of the subventricular zone in the fetus and a hypersensitization to the rewarding cocaine. The later alteration seems not due to the hyperreaction of accumbal dopamine to the cocaine.