PET IMAGING & COCAINE NEUROPHARMACOLOGY IN MONKEYS

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。 治疗可卡因成瘾的有效药物的开发将取决于对可卡因神经药理学的更好理解。目前的项目利用非人类灵长类动物的正电子发射断层扫描(PET)神经成像技术，作为一种非侵入性方法来研究可卡因诱导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体(DAT)抑制剂和选择性5-羟色胺转运体(SERT)抑制剂在可卡因自身给药中的相互作用。我们完成了一系列研究，以确定3，4-亚甲基二氧基甲基苯丙胺(MDMA)的神经药理学特征，MDMA是一种滥用的苯丙胺类兴奋剂。MDMA的对映体似乎有不同的作用，(+)MDMA主要是多巴胺能的，(-)MDMA主要是5-羟色胺能的。有趣的是，(+)MDMA在恢复已熄灭的苯丙胺自我给药作为药物复发的模型方面是有效的。它还引起细胞外多巴胺的强劲增加，安非他明和可卡因也有同样的效果。相反，(-)MDMA在恢复和增加多巴胺方面无效。然而，它在提高血浆催乳素水平方面非常有效，这一效果与5-羟色胺能激动剂相同。这可能解释了MDMA在人类中的独特药理作用。我们在清醒猴子的功能磁共振成像方面取得了重大进展，以便在神经回路水平上表征可卡因和线索诱导的大脑激活。总之，这些结果对于开发替代激动剂药物疗法来治疗兴奋剂滥用具有重要的意义。

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.