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。脑啡肽 作用于Mu-阿片受体，这些受体高度表达 在胎儿猴子的大脑里。此外，孕期接触可卡因 在第70天降低MU受体的mRNA浓度 间脑。我们之前已经发现多巴胺转运体 (DAT)mRNA在45d的中脑中含量很低 胎儿。到妊娠60天时，脑组织中DAT mRNA的浓度 中脑高度增加。我们的假设是可卡因导致 中脑-头端前脑多巴胺的发育变化 通过与发育中的DAT结合而产生的神经回路，从而 改变这个系统的正常运作。为了检验这一假设， 我们测量了DAT结合位点的分布，并对 妊娠第22天至第70天可卡因治疗的效果。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 治疗显著增加了VTA中的配体结合部位。 目前研究的目的是检查更长期的影响 产前可卡因暴露的情况，并评估与 中脑-吻侧前脑多巴胺能神经元的长期变化 神经回路。这些研究的结果将提供重要的 关于灵长类中枢神经正常发育的信息 并帮助我们更好地理解 子宫内接触可卡因。

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. Enkephalin acts at mu-opioid receptors and these receptors are highly expressed in the fetal monkey brain. Moreover, gestational cocaine exposure decreased the mRNA concentration of mu receptors in the day 70 diencephalon. 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 highly increased. Our hypothesis is that cocaine causes the developmental changes in the midbrain-rostral forebrain dopamine neurocircuitry through binding to the developing DAT, and thereby altering normal functioning of this system. To test this hypothesis, we measured the distribution of DAT binding sites and quantified the effects of cocaine treatment from day 22 to day 70 of gestation. 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 the ligand binding sites in the VTA. The aim of current studies are 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 central nervous system and help increase our understanding of the consequences of in utero cocaine exposure.