EFFECTS OF COCAINE IN FETAL MONKEY BRAIN

可卡因对胎猴大脑的影响

• 批准号: 6116109
• 负责人: OLINE K RXNNEKLEIV
• 金额: $ 8.93万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116109
• 关键词: Mammalia; animal tissue; bioimaging /biomedical imaging; clinical research; endocrine gland /system; growth /development; microscopy; nervous system; radiography; reproductive system; substance abuse related disorder; ultrasonography; women's health

We have developed a rhesus monkey model to study the ontogeny of the midbrain-rostral forebrain dopamine circuitry, and have used this model to study the consequences of gestational cocaine exposure. Fetuses from these pregnancies develop a repertoire of neural deficiencies including decreased mRNA expression of tyrosine hydroxylase in the midbrain and increased mRNA expression and binding densities of dopamine receptor subtypes in the rostral forebrain. In addition, maternal exposure to cocaine increases gene expression of dynorphin and enkephalin in presumed dopamine target neurons in the rostral forebrain at both day 60 and day 70 of gestation. These findings provide further evidence for a disrupted dopamine input to the striatal area of the cocaine exposed fetus. We have found previously that dopamine transporter (DAT) mRNA is present in low quantities in the midbrain of day 45 fetuses. By day 60 of gestation, the concentration of DAT mRNA in the midbrain is h ighly incr eased. Since cocaine may cause the neurological changes through an action at the DAT, we evaluated whether DAT mRNA and binding sites were present in the day 70 fetal primate. We also explored whether gestational cocaine exposure had an effect on the expression of DAT in the fetal brain, using quantitative autoradiography with the selective, high affinity DAT ligand [125I]-RTI-121 and in situ hybridization for DAT mRNA. We found that [125I]-RTI-121 binding to the DAT were highest in the substantia nigra and the ventral tegmental area (VTA), and cocaine treatment significantly increased DAT mRNA expression and ligand binding sites in the fetal midbrain. The aim of current studies is to examine the more long-term effects of prenatal cocaine exposure and to assess the mechanisms involved in long-term changes of the midbrain-rostral forebrain dopaminergic neurocircuitry. The results from these studies will provide important information about normal development of the primate cent ral nervous system and help increase our understanding of the consequences of in utero cocaine exposure. FUNDING NIH DA07165 PUBLICATIONS Rxnnekleiv OK, Fang Y, Choi WS, Chai L. Changes in the midbrain-rostral forebrain dopamine circuitry in the cocaine-exposed primate fetal brain. Ann NY Acad Sci 846:165-182, 1998. Fang Y, Bosch MA, Rxnnekleiv OK. Dopamine transporter binding sites in fetal rhesus monkey brain Effects of gestational cocaine on [125]-RTI-121 binding densities. Soc Neurosci. Abstr 24:1966, 1998. Lai W, Bosch MA, Naylor BR, Kelly MJ, Rxnnekleiv OK. Alterations in the expression of fetal myocardial gap junctional proteins as a result of in utero exposure to cocaine. Soc Neurosci Abstr 24:872, 1998. Fang Y, Lu N, Rxnnekleiv OK. Mu-opioid receptor-stimulated [35S]GTP?S autoradiography in fetal monkey brain Effect of prenatal cocaine exposure. In 29th International Narcotics Research Conference, Garmisch-Partenkirchen, Germany. INRC Abstr 29:56, 1998.

我们已经开发了一个恒河猴模型来研究 中脑 - 罗马前脑多巴胺电路，并使用了 研究妊娠可卡因暴露的后果的模型。 这些怀孕的胎儿发展了神经的曲目 缺陷包括酪氨酸的mRNA表达降低 中脑中的羟化酶并增加mRNA表达和结合 the前脑中多巴胺受体亚型的密度。 在 此外，母体暴露于可卡因会增加基因表达 在假定的多巴胺靶神经元中的Dynorphin和Enkephalin 妊娠的第60天和第70天的前脑前脑。 这些 调查结果提供了进一步的证据，证明了多巴胺输入的破坏 可卡因暴露的胎儿的纹状体区域。 我们找到了 以前，多巴胺转运蛋白（DAT）mRNA存在于低 第45天的中脑中的数量。 到妊娠第60天， 中脑中DAT mRNA的浓度逐渐降低。 由于可卡因可能会通过在 DAT，我们评估了是否存在DAT mRNA和绑定位点 在第70天的胎儿灵长类动物。 我们还探索了妊娠是否 可卡因暴露对胎儿中DAT的表达有影响 大脑，使用定量放射自显影和选择性高 亲和力DAT配体[125i] -rti-121和dat的原位杂交 mRNA。 我们发现[125i] -rti-121与DAT结合最高 黑质尼格拉和腹侧盖区（VTA）和可卡因 治疗显着增加了DAT mRNA表达和配体 胎儿中脑的结合位点。 当前研究的目的是 检查产前可卡因暴露的长期影响和 评估与长期变化有关的机制 中脑 - 罗马前脑多巴胺能神经记录。 结果 从这些研究中将提供有关正常的重要信息 发展灵长类动物的神经系统并有助于增加 我们对子宫可卡因暴露的后果的理解。 资助NIH DA07165出版物rxnnekleiv OK，Fang Y，Choi WS，Chai L.中脑 - 波拉兰前脑多巴胺电路的变化 可卡因暴露的灵长类动物胎儿大脑。 Ann NY Acad Sci 846：165-182， 1998。FangY，Bosch MA，RXNNEKLEIV OK。 多巴胺转运蛋白结合 胎儿鼠尾草大脑妊娠可卡因的作用 [125] -RTI-121结合密度。 Soc Neurosci。 Abstr 24：1966，1998。 Lai W，Bosch MA，Naylor BR，Kelly MJ，Rxnnekleiv OK。 改变 结果，胎儿心肌间隙连接蛋白的表达 在子宫内暴露于可卡因。 Soc Neurosci Abstr 24：872，1998。 Fang Y，Lu N，Rxnnekleiv OK。 mu阿片受体刺激[35S] GTP？s 产前可卡因的胎儿猴脑效应的放射自显影 接触。 在第29届国际麻醉品研究会议上 德国Garmisch-Partenkirchen。 INRC ABSTR 29：56，1998。