Yanai Joseph, Huleihel Rabab, Izrael Michal, Metsuyanim Sally, Shahak Halit, Vatury Ori, Yaniv Shiri P
The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University - Hadassah Medical School, Box 12272, 91120 Jerusalem, Israel.
Int J Neuropsychopharmacol. 2003 Sep;6(3):253-65. doi: 10.1017/S1461145703003523.
Opioid drugs act primarily on the opiate receptors; they also exert their effect on other innervations resulting in non-opioidergic behavioural deficits. Similarly, opioid neurobehavioural teratogenicity is attested in numerous behaviours and neural processes which hinder the research on the mechanisms involved. Therefore, in order to be able to ascertain the mechanism we have established an animal (mouse) model for the teratogenicity induced by opioid abuse, which focused on behaviours related to specific brain area and innervation. Diacetylmorphine (heroin) and not morphine was applied because heroin exerts a unique action, distinguished from that of morphine. Pregnant mice were exposed to heroin (10 mg/kg per day) and the offspring were tested for behavioural deficits and biochemical alterations related to the septohippocampal cholinergic innervation. Some studies employing the chick embryo were concomitantly added as a control for the confounding indirect variables. Prenatal exposure to heroin in mice induced global hyperactivation both pre- and post-synaptic along the septohippocampal cholinergic innervation, including basal protein kinase C (PKC) activity accompanied by a desensitization of PKC activity in response to cholinergic agonist. Functionally, the heroin-exposed offspring displayed deficits in hippocampus-related behaviours, suggesting deficits in the net output of the septohippocampal cholinergic innervation. Grafting of cholinergic cells to the impaired hippocampus reversed both pre- and post-synaptic hyperactivity, resensitized PKC activity, and restored the associated behaviours to normality. Consistently, correlation studies point to the relative importance of PKC to the behavioural deficits. The chick model, which dealt with imprinting related to a different brain region, confirmed that the effect of heroin is direct. Taken together with studies by others on the effect of prenatal exposure to opioids on the opioidergic innervation and with what is known on the opioid regulation of the cholinergic innervation, it appears that heroin exerts its neuroteratogenicity by inducing alterations in the opioidergic innervation, which by means of its regulatory action, attenuates the functional output of the cholinergic innervation. In our model, there was hyperactivity mostly of the post-synaptic components of the cholinergic innervation. However, the net cholinergic output is decreased because PKC is desensitized to the effect of the cholinergic agonist, and this is further evidenced by the extensive deficits in the related behaviours.
阿片类药物主要作用于阿片受体；它们也会对其他神经支配产生影响，导致非阿片类神经行为缺陷。同样，阿片类神经行为致畸性在众多行为和神经过程中都得到了证实，这阻碍了对相关机制的研究。因此，为了能够确定其机制，我们建立了一个阿片类药物滥用所致致畸性的动物（小鼠）模型，该模型聚焦于与特定脑区和神经支配相关的行为。使用的是二乙酰吗啡（海洛因）而非吗啡，因为海洛因具有独特的作用，与吗啡不同。将怀孕小鼠暴露于海洛因（每天10毫克/千克），并对其后代进行与隔海马胆碱能神经支配相关的行为缺陷和生化改变测试。同时加入一些使用鸡胚的研究作为混杂间接变量的对照。小鼠产前暴露于海洛因会导致隔海马胆碱能神经支配的突触前和突触后整体过度激活，包括基础蛋白激酶C（PKC）活性，同时PKC活性对胆碱能激动剂的反应出现脱敏。在功能上，暴露于海洛因的后代在与海马相关的行为上表现出缺陷，这表明隔海马胆碱能神经支配的净输出存在缺陷。将胆碱能细胞移植到受损的海马中可逆转突触前和突触后的过度活跃，使PKC活性重新敏感化，并使相关行为恢复正常。一致地，相关性研究指出PKC对行为缺陷的相对重要性。处理与不同脑区相关印记的鸡胚模型证实了海洛因的作用是直接的。结合其他人关于产前暴露于阿片类药物对阿片类神经支配的影响的研究以及已知的阿片类药物对胆碱能神经支配的调节作用，似乎海洛因通过诱导阿片类神经支配的改变来发挥其神经致畸性，这种改变通过其调节作用减弱了胆碱能神经支配的功能输出。在我们的模型中，胆碱能神经支配的突触后成分大多存在过度活跃。然而，胆碱能净输出减少，因为PKC对胆碱能激动剂的作用脱敏，相关行为的广泛缺陷进一步证明了这一点。
