PET IMAGING & COCAINE NEUROPHARMACOLOGY IN MONKEYS

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。 开发治疗可卡因成瘾的有效药物将取决于对可卡因神经药理学的更好理解。目前的项目利用正电子发射断层扫描（PET）神经成像技术在非人类灵长类动物作为一种非侵入性的方法来研究可卡因引起的中枢神经系统活动的功能变化。主要的重点是选择性多巴胺转运蛋白（DAT）抑制剂和选择性5-羟色胺转运蛋白（SERT）抑制剂之间的相互作用可卡因自我管理。我们完成了一系列研究，以表征3，4-亚甲二氧基甲基苯丙胺（MDMA），滥用安非他明类兴奋剂的神经药理学。MDMA的对映体似乎具有不同的作用，（+）MDMA主要是多巴胺能，（-）MDMA主要是多巴胺能。有趣的是，（+）MDMA是有效的恢复熄灭安非他明自我管理作为一个模型的药物复吸。它还诱导细胞外多巴胺的强烈增加，这是安非他明和可卡因共有的效果。相反，（-）MDMA在恢复和增加多巴胺方面无效。然而，它在增加血浆催乳素水平方面非常有效，这是一种与α-肾上腺素能激动剂共有的作用。这可能解释了MDMA在人类中的独特药理学。我们在清醒猴子的功能磁共振成像的发展中取得了重大进展，以表征可卡因和线索诱导的大脑激活在神经回路水平。总的来说，这些结果对开发替代激动剂药物治疗兴奋剂滥用具有重要意义。

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. The development of effective medications to treat cocaine addiction will depend on a better understanding of cocaine neuropharmacology. The current project utilized positron emission tomography (PET) neuroimaging techniques in nonhuman primates as a noninvasive approach to investigate cocaine-induced functional changes in central nervous system activity. The major emphasis has been on interactions between selective dopamine transporter (DAT) inhibitors and selective serotonin transporter (SERT) inhibitors on cocaine self-administration. We completed a series of studies to characterize the neuropharmacology of 3,4-methylenedioxymethamphetamine (MDMA), an abused amphetamine-type stimulant. The enantiomers of MDMA appear to have differential effects with (+)MDMA being primarily dopaminergic and (-)MDMA being primarily serotonergic. Interestingly, (+)MDMA was effective in reinstating extinguished amphetamine self-administration as a model of drug relapse. It also induced robust increases in extracellular dopamine, an effect shared by amphetamine and cocaine. In contrast, (-)MDMA was ineffective in reinstatement and in increasing dopamine. However, it was very effective in increasing plasma prolactin levels, an effect that is shared by serotonergic agonists. This may explain the unique pharmacology of MDMA in humans. We made significant progress in the development of fMRI in awake monkeys in order to characterize cocaine- and cue-induced brain activation at a neurocircuitry level. Collectively, the results have important implication concerning the development of substitute agonist pharmacotherapies to treat stimulant abuse.