Cutler A R, Wilkerson A E, Gingras J L, Levin E D
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Neurotoxicol Teratol. 1996 Nov-Dec;18(6):635-43. doi: 10.1016/s0892-0362(96)00125-0.
Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8-20); nicotine (4 mg/kg/day continuous SC infusion on GD 4-20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the beta-noradrenergic antagonist propranolol (10-20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13-42% and offspring birth weight was reduced by 7-12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1-5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.
产前接触可卡因或尼古丁会产生多种致畸效应。本研究旨在确定它们单独及联合作用对认知功能和性分化的影响。将19只怀孕的Long-Evans大鼠分为以下几组：单独接触可卡因组（在妊娠第8至20天，皮下注射，剂量为15 mg/kg，每日两次）；单独接触尼古丁组（在妊娠第4至20天，皮下持续输注，剂量为4 mg/kg/天）；同时接触尼古丁和可卡因组；以及仅给予赋形剂组。所有幼崽出生时测量其出生体重和肛门生殖器距离（AGD）。在青春期前和青春期，通过连续五天每天进行一次，以及一周后进行第六次试验，在莫里斯水迷宫（MWM）中测试学习和记忆能力；在成年期，在放射状臂迷宫（RAM）中进行测试。在RAM中，习得训练后给予β-去甲肾上腺素能拮抗剂普萘洛尔（10 - 20 mg/kg）进行药物激发试验。与对照组相比，所有三个暴露组的母体体重增加减少了13 - 42%，后代出生体重减少了7 - 12%。与未接触可卡因的雄性幼崽（2.88 mm）相比，可卡因使雄性幼崽的AGD降低（2.68 mm）（p < 0.025）。在对AGD测量值进行体重校正后，也观察到了可卡因的性别选择性效应。采用此测量方法，经可卡因处理的雌性幼崽的AGD显著高于未接触可卡因的雌性幼崽（p < 0.05）。在MWM中，有两种类型的试验：线索参考记忆试验和非线索空间工作记忆试验。在线索参考记忆试验中，仅在第一次试验中观察到可卡因显著延长潜伏期。在空间工作记忆试验中，在第1至5天的每日训练中均观察到可卡因延长潜伏期，但在一周后的第6天保留试验中未观察到。在RAM习得过程中，各暴露组之间的选择准确性没有显著差异。在普萘洛尔激发试验后，产前接触可卡因或尼古丁的大鼠表现出选择准确性缺陷。这些大鼠对普萘洛尔没有任何反应，而对照组的选择准确性略有提高。本研究结果表明，产前接触可卡因会改变MWM基础条件下的长期认知功能以及RAM中的药物激发试验结果、出生体重和生殖器发育。可卡因引起的认知缺陷主要表现在工作记忆方面，而非参考记忆或长期记忆。仅观察到产前接触尼古丁会改变出生体重以及RAM中对普萘洛尔激发试验的认知功能反应。
