COCAINE USE & MONOAMINE FUNCTION IN NON HUMAN PRIMATES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目前迫切需要开发有效的药物来治疗可卡因成瘾。在静脉给药的非人灵长类动物模型中，确定了减少可卡因使用的药物效果。该项目继续侧重于单胺转运体抑制剂的行为药理学和体内神经化学，作为描述可卡因神经药理学特征的补充方法。此外，我们还强调了谷氨酸和多巴胺之间的行为和神经化学相互作用。谷氨酸受体激动剂LY379268可有效阻断可卡因的行为兴奋、增强和恢复(复发)效应。体内微透析的补充神经化学研究表明，LY379268还有效地阻断可卡因诱导的细胞外多巴胺增加，这是药物相互作用影响行为的潜在机制。我们已经开始研究对多巴胺和5-羟色胺受体具有不同亲和力的单胺释放剂。结果表明，具有高释放5-羟色胺能力的化合物具有低滥用倾向的行为特征。我们继续开发一种新的方案来研究药物诱导的自我管理行为的恢复(复发)，该方案消除了主动灭绝学习的需要，并在人类中建立了更好的药物戒断模型。非人灵长类动物体内神经化学和行为药理学的整合将确定可卡因和相关刺激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。此外，全面评估谷氨酸和多巴胺之间的相互作用对于理解和治疗包括精神分裂症、帕金森病和焦虑症在内的各种神经和精神疾病具有重要意义。

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. here 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. The glutamate receptor agonist, LY379268, was effective in blocking the behavioral-stimulant, reinforcing and reinstatement (relapse) effects of cocaine. Complementary neurochemical studies with in vivo microdialysis indicated that LY379268 was also effective in blocking cocaine-induced increases in extracellular dopamine, a potential mechanism underlying drug interactions on behavior. We have initiated studies with monoamine releasers having different affinity for dopamine and serotonin receptors. The results indicate that compounds with high potency for serotonin release have a behavioral profile of low abuse liability. We continue to develop a novel protocol to study drug-induced reinstatement (relapse) of self-administration behavior that eliminates the need for active extinction learning and better models drug abstinence in humans. 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. Moreover, a comprehensive evaluation of interactions between glutamate and dopamine should have significant implications toward understanding and treating a variety of neurological and psychiatric disorders including schizophrenia, Parkinson's disease and anxiety disorders.