Marczynski T J, Hawkins M C, Swann P G, Krivograd A F, Patel M K, Dugich M
Department of Pharmacology, University of Illinois at the Medical Center, Chicago 60612.
Neurotoxicol Teratol. 1988 Mar-Apr;10(2):101-11. doi: 10.1016/0892-0362(88)90073-6.
Pregnant and subsequently lactating rats had ad lib access to drinking water which contained either a benzodiazepine antagonist, Ro 15-1788 or diazepam (DZ). On the average, the rats consumed 2.9 mg/kg/day of Ro 15-1788 or 5.3 mg/kg/day of diazepam over the time period of 3 weeks, from gestation day 14 through postpartum day 14. The control group consumed equivalent volumes of the drug vehicle in water. While Ro 15-1788 had no apparent toxic effects, the numbers of viable pups in the DZ group were significantly reduced. The mean weight of the viable pups, and their gross behavior were not different in all three groups. However, the fully mature 4.5-month-old male progenies exposed to Ro 15-1788 were much more efficient in the radial arm maze test than the control or the diazepam-exposed animals; they rapidly habituated to the novel environment, their exploratory activity was uninhibited by distracting visual and auditory stimuli, they made fewer "working memory" errors in collecting baits, had a much better control over their emotional responses and the autonomic nervous system, as shown by very low defecation/urination scores, and, at the age of 5 months, they had a significant (66%) increase in the density of benzodiazepine receptors in the hippocampal formation, as compared to the control or the diazepam-exposed progenies. In conclusion, the upregulation of benzodiazepine receptor ontogenesis is retained in adult animals and resulted in improved "working memory" and better control over emotional responses that were particularly evident when the animals were challenged by novel and "intimidating" environmental stimuli.
怀孕及随后处于哺乳期的大鼠可随意饮用含有苯二氮䓬拮抗剂Ro 15-1788或地西泮（DZ）的水。从妊娠第14天到产后第14天的3周时间里，大鼠平均每天摄入2.9毫克/千克的Ro 15-1788或5.3毫克/千克的地西泮。对照组饮用等量含药物赋形剂的水。虽然Ro 15-1788没有明显的毒性作用，但地西泮组的存活幼崽数量显著减少。三组中存活幼崽的平均体重及其总体行为没有差异。然而，接触Ro 15-1788的4.5个月大的完全成熟雄性后代在放射状臂迷宫试验中比对照组或接触地西泮的动物效率更高；它们能迅速适应新环境，其探索活动不受干扰性视觉和听觉刺激的抑制，在收集诱饵时犯的“工作记忆”错误更少，对情绪反应和自主神经系统的控制更好，排便/排尿分数很低就表明了这一点，并且在5个月大时，与对照组或接触地西泮的后代相比，它们海马结构中苯二氮䓬受体的密度显著增加（66%）。总之，苯二氮䓬受体个体发生的上调在成年动物中得以保留，并导致“工作记忆”改善以及对情绪反应的更好控制，当动物受到新的和“令人生畏”的环境刺激挑战时，这一点尤为明显。
