MECHANISMS OF COCAINE ACTION ON THE DEVELOPING BRAIN

在宫内接触可卡因的新生儿表现出行为和 可能阻碍其后续发育的神经异常。 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，最容易从神经生物学研究中获得的大脑 动物。我们实验室以前的研究是以大鼠为模型的 动物研究表明，可卡因结合部位存在于胎儿大脑和 可卡因对突触多巴胺(DA)摄取的抑制作用发生在产前， 但可卡因并不会强烈地抑制儿茶酚胺的合成，因为它 成年人是这样做的。产前接触可卡因的有害影响可能 产生的部分原因是药物与这些结合部位的相互作用 随后对单胺能发育的干扰。因此， 拟议研究的总体目标是进一步界定 可卡因的产前作用机制，探讨神经化学 孕期慢性可卡因治疗的影响及其相互关系 可卡因暴露的动物可能发生的行为变化。 具体地说，我们首先要确定的是， 可卡因受体在出生前和出生后及其定位 利用新上市的可卡因模拟井~3H-CFT进行放射自显影 适合于约束性研究。因为成年生物体中的可卡因受体 与DA、去甲肾上腺素(NE)和 5-羟色胺(5-HT)，我们将通过以下方式在胎儿中寻找类似的关系 观察单胺能神经末梢减少化的效果 选择性神经毒素，并与突触体的药物抑制相关 单胺摄取与CFT结合的抑制。因为中央 摄取抑制在生理和行为调节中的作用 可卡因的影响，我们将研究可卡因对胎儿发育的影响 突触体摄取过程或DA、NE和5-羟色胺，并确定 可卡因在这些过程中的个体发育及其在不同阶段的效力 发育阶段。最后，我们将调查短期和长期- 慢性产前可卡因治疗对可卡因受体的远期影响 递质摄取系统与可卡因、D1和D2的摄取抑制 受体，以及可卡因和可卡因刺激的选定行为 由多巴胺能机制介导。可卡因的抑制作用 隔离导致的痛苦发声将在产前进行研究 暴露在可卡因中的幼崽，而其他动物成年后会 使用静脉注射进行位置调节测试。可卡因注射作为 增强剂。通过检测一系列相关的神经化学参数 以及可卡因刺激的行为反应在我们的产前- 经过治疗的受试者，我们希望找到特定的神经改变， 对动物产生明显的功能后果。

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.