EFFECTS OF COCAINE IN FETAL MONKEY BRAIN

我们已经建立了一种恒河猴模型来研究糖尿病的个体发育 中脑-头端前脑的多巴胺回路，并使用了 模型来研究孕期可卡因暴露的后果。 这些妊娠的胎儿发育出一套神经系统 包括酪氨酸mRNA表达降低在内的缺陷 中脑中的羟基酶与增加的mRNA表达和结合 前脑吻侧多巴胺受体亚型的密度。在……里面 此外，母亲接触可卡因会增加基因表达 强啡肽和脑啡肽在大鼠脑内可能的多巴胺靶向神经元中的表达 在妊娠60天和70天时，前脑的吻侧。这些 研究结果提供了进一步的证据，证明多巴胺在脑内的输入受到干扰 暴露在可卡因中的胎儿纹状体区域。我们发现了 以前，多巴胺转运体(DAT)的mRNA存在于低水平 45天胎儿中脑的数量。在怀孕60天时， 中脑组织中DAT基因的浓度显著增加。 因为可卡因可能通过作用于 DAT，我们评估是否存在DAT mRNA和结合位点 在第70天，胎儿灵长类。我们还探索了是否怀孕 可卡因暴露对胎儿脑组织DAT表达的影响 大脑，使用定量放射自显影具有选择性，高 亲和DAT配体[125I]-RTI-121及原位杂交检测DAT MRNA.我们发现与DAT结合的[125I]-RTI-121在 黑质和腹侧被盖区与可卡因 治疗后DAT基因表达和配体显著增加 胎儿中脑中的结合部位。当前研究的目的是 检查产前暴露可卡因的更长期影响，并 评估长期变化所涉及的机制 中脑-头端前脑多巴胺能神经回路。结果是 这些研究将提供有关正常的重要信息 灵长类中枢神经系统的发育和帮助增加 我们对宫内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.大鼠中脑-吻侧前脑多巴胺环路的变化 暴露在可卡因中的灵长类动物胎儿大脑。《纽约艺术与科学》846：165-182 1998年。方Y，博世MA，Rxnnekleiv OK。多巴胺转运体结合 孕期可卡因对胚胎恒河猴脑内各部位的影响 [125]-RTI-121结合密度。SoC Neurosci。字母24：1966,1998。 Lai W，Bosch MA，Nayler BR，Kelly MJ，Rxnnekleiv OK。中的更改 胎儿心肌缝隙连接蛋白的表达 宫内接触可卡因的风险。《神经科学报》摘录24：872,1998。 方毅，陆南，Rxnnekleiv好的。MU-阿片受体刺激的[35S]GTP？S 胎猴脑放射自显影对胎儿期可卡因的影响 曝光。在第29届国际毒品研究大会上， 加米施-帕滕基兴，德国。INRC：29：56,1998。

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.