Prenatal cocaine exposure alters signal transduction in the brain D1 dopamine receptor system
Prenatal cocaine exposure alters signal transduction in the brain D1 dopamine receptor system
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DOI：
10.1111/j.1749-6632.1998.tb09741.x
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发表时间：
1998-01-01
期刊：
影响因子：
--
通讯作者：
Wang, HY
中科院分区：
文献类型：
--
作者：
Friedman, E;Wang, HY
妊娠期间使用可卡因可能导致新生儿持续的行为异常。动物研究表明，产前接触可卡因的后代的行为和神经化学变化。单胺神经元，包括含有多巴胺的神经元，在产前出现并开始运作，并在出生后早期成熟。因此，可以想象，怀孕期间接触可卡因可能严重影响正常发育，随后导致长期的产后神经化学和行为变化。我们获得的数据表明，产前暴露于可卡因在兔损害信号转导通过D-1，但不是D-2多巴胺受体系统。这反映在兔后代的皮质和纹状体中多巴胺刺激的[S-35]GTP γ S与G α s的结合受损，而不影响核苷酸与G α i的结合。随着给予妊娠母鼠可卡因剂量的增加，D-1多巴胺受体介导的Gs蛋白活化的选择性降低的严重程度增加。每日两次注射3 mg/kg盐酸可卡因治疗后观察到最大损害。多巴胺刺激的GTP与G α结合的减少不是由于膜G α蛋白或D-1多巴胺受体浓度的降低。数据还表明，在子宫内可卡因暴露导致持久的解偶联的D-1多巴胺受体从其相关的Gs蛋白，出现早在妊娠第22天，并持续到出生后第100天。D-1多巴胺受体介导的信号转导的减少可能是由D-1多巴胺受体或Gs α的翻译后修饰介导的，如磷酸化，这导致这些膜组分之间的偶联改变。由此产生的衰减的D-1多巴胺受体介导的信号可能最终的基础持久的行为功能障碍和形态学变化，这是与产前可卡因暴露在兔子。
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-1 but not the D-2 dopamine receptor system. This is reflected in impaired dopamine-stimulated [S-35]GTP gamma S binding to G alpha s without affecting binding of the nucleotide to G alpha i in both cortex and striatum of rabbit offspring. This selective reduction in D-1 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 HCl. The reduction in dopamine-stimulated GTP binding to G alpha s did not result from a decrease in concentration of membrane G alpha s protein or D-1 dopamine receptors. The data also indicate that in utero cocaine exposure causes persistent uncoupling of the D-1 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-1 dopamine receptor-mediated signal transduction may be mediated by posttranslational modifications of the D-1 dopamine receptor or of Gs alpha such as phosphorylation, which result in altered coupling between these membrane components. The resultant attenuated D-1 dopamine receptor-mediated signaling may ultimately underlie both longlasting behavioral dysfunction and morphologic changes which are associated with prenatal cocaine exposure in the rabbit.