Effects of mGluR2/3 Activation on Cue-Induced Cocaine Relapse in Squirrel Monkeys

描述(申请人提供)：尽管做出了很大的努力，但目前还没有FDA批准的药物疗法可用于治疗可卡因滥用或依赖。吸食可卡因的一个突出特点是成瘾者的复吸率很高。可卡因渴求被认为是复发前的一项重要事件，并可通过呈现与可卡因相关的线索在人类成瘾者中引发。同样，可卡因配对线索能够在经过自我管理可卡因训练的实验动物中恢复之前熄灭的寻找可卡因的行为。最近在啮齿动物身上获得的证据表明，第二组代谢性谷氨酸受体(MGluRs)的激活能够减弱可卡因诱导恢复的能力。第二组mGluRs包括mGluR2和mGluRs亚型，是Gi/o偶联的突触前受体，其激活导致谷氨酸、多巴胺和其他神经递质的突触释放减少。这些受体定位于已知参与可卡因增强效应的大脑区域，如尾状核、伏隔核(NAcc)、前额叶皮质和杏仁核。拟议的实验试图将啮齿类动物的早期发现转化为可卡因使用和复发的非人类灵长类动物模型。松鼠猴子将被训练在不同的环境刺激下自我静脉注射可卡因。因此，在盐水替代试验中呈现这些刺激将导致仅通过呈现与可卡因配对的线索而不是通过可卡因本身的直接药理作用来启动和维持可卡因寻找行为。在线索呈现测试之前，动物将被高选择性和有效的II组mGluR激动剂LY379268预处理，以确定这些受体的激活是否可以减弱线索诱导的灵长类动物的药物寻找行为，这些灵长类动物有广泛的可卡因自我给药史。随后，动物将被植入指向纹状体背侧和腹侧(NAcc)部分的引导套管。提示呈现测试将与微透析同时进行，以评估LY379268对可卡因寻找的影响与其对背侧和腹侧纹状体细胞外多巴胺或谷氨酸水平的神经药理学影响之间的任何可能的相关性。本研究的目的是为了更好地了解毒品相关线索能够在可卡因成瘾者中引发药物渴求的机制(S)。由于渴求是吸毒复发前的一个主要因素，这些实验的结果可能有助于确定抗复发和预防复发药物开发的新靶点。

DESCRIPTION (provided by applicant): Despite substantial efforts, there are currently no FDA-approved pharmacotherapies available for the treatment of cocaine abuse or dependence. A prominent feature of cocaine use is the high rate of relapse among addicted individuals. Cocaine craving is thought to serve as an important event preceding relapse and can be elicited in human addicts via presentation of cocaine-associated cues. Similarly, cocaine-paired cues are capable of reinstating previously-extinguished cocaine-seeking behavior in experimental animals trained to self-administer cocaine. Recent evidence obtained in rodents has suggested that activation of group II metabotropic glutamate receptors (mGluRs) is capable of attenuating the ability of cocaine cues to induce reinstatement. Group II mGluRs include the mGluR2 and mGluRS subtypes and are Gi/o-coupled presynaptic receptors whose activation results in decreased synaptic release of glutamate, dopamine, and other neurotransmitters. These receptors are localized in brain regions known to be involved in the reinforcing effects of cocaine, such as the caudate nucleus, nucleus accumbens (NAcc), prefrontal cortex, and amygdala. The proposed experiments seek to translate and extend earlier findings from rodents to nonhuman primate models of cocaine use and relapse. Squirrel monkeys will be trained to self-administer intravenous cocaine in the presence of distinct environmental stimuli. Presentation of these stimuli during saline substitution tests will thus result in cocaine-seeking behavior initiated and maintained solely by the presentation of cocaine-paired cues and not by the direct pharmacological effects of cocaine itself. Animals will be pretreated with the highly-selective and potent group II mGluR agonist LY379268 prior to cue- presentation tests to determine if activation of these receptors can attenuate cue-induced drug-seeking behavior in primates with extensive histories of cocaine self-administration. Subsequently, animals will be implanted with guide cannulae targeting both the dorsal and ventral (NAcc) portions of the striatum. Cue- presentation test sessions will be conducted concurrently with microdialysis to assess any possible correlations between LY379268 effects on cocaine-seeking and its neuropharmacological effects on extracellular dopamine or glutamate levels within the dorsal and ventral striatum. The goal of this research is to better understand the mechanism(s) by which drug-associated cues are capable of eliciting drug-craving in cocaine-addicted individuals. As craving is a major factor preceding relapse to drug use, the results of these experiments may help identify new targets for anticraving and relapse-prevention medications development.