MECHANISMS OF COCAINE ACTION ON THE DEVELOPING BRAIN

宫内接触可卡因的新生儿表现出行为和 神经系统异常，可能会阻碍他们随后的发展。 使临床医生能够有效地预测和治疗这些缺陷 需要了解可卡因对胎儿的作用机制 大脑，这可以最容易地从神经生物学研究中获得， 动物 我们实验室以前用大鼠作为模型的研究 动物已经表明，可卡因结合位点存在于胎儿脑中， 可卡因对突触多巴胺（DA）摄取的抑制发生在产前， 但可卡因并不能强烈抑制儿茶酚胺的合成， 在成年人身上。 产前接触可卡因的有害影响可能 部分由药物与这些结合位点的相互作用引起， 随后干扰单胺能发育。 因此 拟议研究的总体目标是进一步确定 可卡因作用的产前机制，以研究神经化学 慢性产前可卡因治疗的影响，并将这些影响 可卡因暴露动物可能的行为改变。 具体来说，我们将首先确定的动力学特性， 可卡因受体在出生前和出生后，并定位这些受体 放射自显影使用3 H-CFT，一种新的可用的可卡因类似物， 适用于绑定研究。 就像成年生物体内的可卡因受体 与DA、去甲肾上腺素（NE）和 5-羟色胺（5-HT），我们将通过以下方法在胎儿中寻找类似的关系： 检查减少单胺能神经末梢的作用， 选择性神经毒素，并通过相关的药物抑制突触体 抑制CFT结合的单胺摄取。 因中央 摄取抑制在介导生理和行为 可卡因的影响，我们将研究产前发育的 突触体摄取过程或DA，NE和5-HT，并确定 可卡因对这些过程的作用及其在各种情况下的效力 发育阶段 最后，我们将研究短期和长期- 长期产前可卡因治疗对可卡因受体的影响， 递质摄取系统和可卡因、D1和D2的摄取抑制 受体，以及由可卡因刺激的特定行为， 由多巴胺能机制介导。 可卡因抑制 隔离引起的痛苦发声将在产前研究 可卡因暴露的幼崽，而其他动物保持到成年， 使用静脉注射可卡因作为 - 好的 通过检查大量相关的神经化学参数 沿着可卡因刺激的行为反应， 治疗的受试者，我们希望找到特定的神经改变， 对动物有明显的功能影响。

Newborn infants exposed to cocaine in utero exhibit behavioral and neurological abnormalities that may hamper their subsequent development. Enabling clinicians to effectively predict and treat these deficits requires knowledge about the mechanisms of cocaine action on the fetal brain, which can be obtained most readily from neurobiological research on animals. Previous studies in our laboratory using the rat as a model animal have shown that cocaine binding sites are present in fetal brain and that cocaine inhibition of synaptic dopamine (DA) uptake occurs prenatally, but that cocaine does not acutely inhibit catecholamine synthesis as it does in adults. The deleterious effects of prenatal cocaine exposure may arise in part from interaction of the drug with these binding sites and subsequent interference with monoaminergic development. Therefore, the overall goals of the proposed studies are to further define the fundamental prenatal mechanisms of cocaine action, to investigate the neurochemical affects of chronic prenatal cocaine treatment, and to relate these effects to possible behavioral alterations in cocaine-exposed animals. Specifically, we will first determine the kinetic characteristics of cocaine receptors pre- and postnatally and localize these receptors autoradiographically using 3H-CFT, a newly available cocaine analog well suited for binding studies. As cocaine receptors in adult organisms have been related to membrane transport systems for DA, norepinephrine (NE), and serotonin (5-HT), we will look for a similar relationship in fetuses by examining the effects of lessening monoaminergic nerve terminals with selective neurotoxins, and by correlating drug inhibition of synaptosomal monoamine uptake with inhibition of CFT binding. Because of the central role of uptake inhibition in mediating the physiological and behavioral effects of cocaine, we will study the prenatal developmental of synaptosomal uptake processes or DA, NE, and 5-HT, and determine the ontogeny of cocaine action on these processes and its potency at various developmental stages. Finally, we will investigate the short- and long- term effects of chronic prenatal cocaine treatment on cocaine receptors, transmitter uptake systems and uptake inhibition by cocaine, D1 and D2 receptors, and selected behaviors that are stimulated by cocaine and mediated by dopaminergic mechanisms. The potency of cocaine in suppressing isolation-induced distress vocalizations will be studied in prenatally cocaine-exposed pups, whereas other animals maintained into adulthood will be tested for place conditioning using i.v. cocaine injection as the reinforcer. By examining a multitude of related neurochemical parameters along with cocaine-stimulated behavioral responses in our prenatally- treated subjects, we expect to find specific neural alterations that have demonstrable functional consequences for the animals.