Friedman Eitan, Wang Hoau-Yan
Division of Molecular Pharmacology, Department of Pharmacology, MCP ◆ Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19129, USA.
Ann N Y Acad Sci. 1998 Jun;846(1):238-247. doi: 10.1111/j.1749-6632.1998.tb09741.x.
Cocaine use during pregnancy may result in persistent behavioral abnormalities in the newborn. Animal studies show behavioral and neurochemical alterations in offspring that were exposed to cocaine prenatally. The monoamine neurons, including those containing dopamine, appear and become operational prenatally and mature during early postnatal life. It is therefore conceivable that exposure to cocaine during gestation may critically affect normal development and subsequently cause protracted postnatal neurochemical and behavioral changes. The data we obtained demonstrate that prenatal exposure to cocaine in the rabbit impairs signal transduction via the D but not the D dopamine receptor system. This is reflected in impaired dopamine-stimulated [S]GTPγS binding to Gαs without affecting binding of the nucleotide to Gαi in both cortex and striatum of rabbit offspring. This selective reduction in D dopamine receptor-mediated activation of Gs protein increased in severity as the dose of cocaine administered to the pregnant dams was increased. Maximal impairment was observed after treatment with two daily injections of 3 mg/kg of cocaine HC1. The reduction in dopamine-stimulated GTP binding to Gαs did not result from a decrease in concentration of membrane Gαs protein or D dopamine receptors. The data also indicate that in utero cocaine exposure causes persistent uncoupling of the D dopamine receptors from their associated Gs protein which appears as early as gestational day 22 and persists to postnatal day 100. The reduction in D dopamine receptor-mediated signal transduction may be mediated by posttranslational modifications of the D dopamine receptor or of Gsα such as phosphorylation, which result in altered coupling between these membrane components. The resultant attenuated D dopamine receptor-mediated signaling may ultimately underlie both long-lasting behavioral dysfunction and morphologic changes which are associated with prenatal cocaine exposure in the rabbit.
孕期使用可卡因可能导致新生儿出现持续性行为异常。动物研究表明，产前接触可卡因的后代会出现行为和神经化学改变。单胺能神经元，包括那些含有多巴胺的神经元，在产前出现并开始发挥作用，在出生后早期成熟。因此，可以想象，孕期接触可卡因可能会严重影响正常发育，随后导致出生后长期的神经化学和行为变化。我们获得的数据表明，兔子产前接触可卡因会损害通过D型而非D型多巴胺受体系统的信号转导。这表现为多巴胺刺激的[S]GTPγS与Gαs的结合受损，而不影响核苷酸与兔子后代皮层和纹状体中Gαi的结合。随着给予怀孕母鼠的可卡因剂量增加，D型多巴胺受体介导的Gs蛋白激活的这种选择性降低会更加严重。在每天注射两次3mg/kg的盐酸可卡因后观察到最大损伤。多巴胺刺激的GTP与Gαs结合的减少并非源于膜Gαs蛋白或D型多巴胺受体浓度的降低。数据还表明，子宫内接触可卡因会导致D型多巴胺受体与其相关的Gs蛋白持续解偶联，这种情况最早在妊娠第22天出现，并持续到出生后第100天。D型多巴胺受体介导的信号转导减少可能是由D型多巴胺受体或Gsα的翻译后修饰（如磷酸化）介导的，这会导致这些膜成分之间的偶联改变。由此产生的D型多巴胺受体介导的信号减弱最终可能是与兔子产前接触可卡因相关的长期行为功能障碍和形态学变化的基础。
