Ryan C L, Pappas B A
Neurobehav Toxicol Teratol. 1986 May-Jun;8(3):279-86.
Primiparous timed-pregnant Wistar dams were administered a single daily SC injection of diazepam (1.0 or 5.0 mg/kg) or vehicle, over gestation days 14-20. The offspring were assessed on a number of developmental parameters. Pups exposed to the lower dose exhibited a decrease in birth weight and a delay in hair growth. Although these parameters were apparently not affected in the higher dose group, a significant dose-dependent decrease in pup viability was observed, both at birth and at one week of age. No differences were manifested for incisor eruption, pinna uncurling, eye opening, righting, geotaxis, acoustic startle, swimming, or forward locomotion. Rotarod performance was affected in the prenatal DZP animals and body weight at 60 days of age was depressed in the males of the 1.0 mg/kg group. The high dose of diazepam produced an increased susceptibility to minor metrazol-induced seizures in a kindling paradigm, but these altered seizure thresholds were not evidenced in an acute metrazol dose-response study. The NE and DA contents of hypothalamus, brainstem, hippocampus, and cortex of adult brains were assessed in each group. DA was not altered in any brain region while a single significant effect on NE was found. In the 1.0 mg/kg exposed rats only males, but not females, showed higher brainstem levels than controls. These results indicate that in the rat, prenatal exposure to clinically relevant doses of diazepam causes both fetal toxicity and long-term neurobehavioral alterations.
初产定时妊娠的Wistar母鼠在妊娠第14至20天每天皮下注射一次地西泮（1.0或5.0毫克/千克）或赋形剂。对后代进行了多项发育参数评估。暴露于较低剂量的幼崽出生体重下降，毛发生长延迟。虽然这些参数在较高剂量组中显然没有受到影响，但在出生时和1周龄时均观察到幼崽存活率呈显著剂量依赖性下降。门齿萌出、耳廓展开、睁眼、翻正、趋地性、听觉惊吓、游泳或向前运动方面没有差异。产前接受地西泮处理的动物的转棒试验表现受到影响，1.0毫克/千克组的雄性在60日龄时体重降低。高剂量地西泮在点燃模型中使对小剂量戊四氮诱发的惊厥易感性增加，但在急性戊四氮剂量反应研究中未发现这些改变的惊厥阈值。对每组成年大脑的下丘脑、脑干、海马体和皮质中的去甲肾上腺素（NE）和多巴胺（DA）含量进行了评估。在任何脑区中DA均未改变，而对NE仅发现单一显著影响。在暴露于1.0毫克/千克的大鼠中，仅雄性而非雌性的脑干水平高于对照组。这些结果表明，在大鼠中，产前暴露于临床相关剂量的地西泮会导致胎儿毒性和长期神经行为改变。
