COCAINE USE & MONOAMINE FUNCTION IN NON HUMAN PRIMATES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 迫切需要开发有效的药物来治疗可卡因成瘾。在非人灵长类动物的静脉内药物自我给药模型中确定了减少可卡因使用的药物有效性。该项目继续侧重于单胺转运蛋白抑制剂的行为药理学和体内神经化学，作为表征可卡因神经药理学的补充方法。此外，我们强调了谷氨酸和多巴胺之间的行为和神经化学相互作用。 最近，我们已经进行了研究与各种单胺释放剂具有不同的亲和力多巴胺和血清素受体。PAL-353，这是更有选择性地释放多巴胺相对于血清素，诱导强大的行为刺激作用类似于安非他明观察到的。相比之下，PAL-313在释放多巴胺和5-羟色胺方面是等效的，在广泛的剂量范围内没有诱导行为刺激作用。即使在显著增加细胞外多巴胺的药物剂量下，这些行为效应的特征差异也是明显的，这支持了这样的解释，即多巴胺能张力的增加可以对运动行为产生突触后抑制效应。我们目前正在表征几种安非他明类似物的强化效果，这些安非他明类似物在释放多巴胺和5-羟色胺的效力上不同。 结果表明，5-羟色胺释放效力高的化合物具有低滥用倾向的行为特征。在非人灵长类动物体内神经化学和行为药理学的整合将定义可卡因和相关兴奋剂成瘾特性的神经化学机制。所获得的结果将指导治疗人类可卡因滥用的努力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is a critical need to develop effective medications to treat cocaine addiction. Medication effectiveness in reducing cocaine use was determined in a nonhuman primate model of intravenous drug self-administration. The project continued to focus on the behavioral pharmacology and in vivo neurochemistry of monoamine transporter inhibitors as complementary approaches to characterize the neuropharmacology of cocaine. In addition, we have emphasized behavioral and neurochemical interactions between glutamate and dopamine. More recently, we have conducted studies with a variety of monoamine releasers having different affinity for dopamine and serotonin receptors. PAL-353, which is more selective for releasing dopamine relative to serotonin, induced robust behavioral-stimulant effects similar to those observed for amphetamine. In contrast, PAL-313, which is equipotent in releasing both dopamine and serotonin, did not induce behavioral-stimulant effects over a broad range of doses. These differences in profile of behavioral effects were evident even at drug doses that markedly increased extracellular dopamine, supporting the interpretation that an increase in serotonergic tone can have a postsynaptic inhibitory effects on motor behavior. We are currently characterizing the reinforcing effectiveness of several amphetamine analogs that differ in potency to release dopamine and serotonin. The results indicate that compounds with high potency for serotonin release have a behavioral profile of low abuse liability. The integration of in vivo neurochemistry and behavioral pharmacology in nonhuman primates will define neurochemical mechanisms that underlie the addictive properties of cocaine and related stimulants. The results obtained will direct efforts to treat cocaine abuse in humans.