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

描述（由申请人提供）：尽管做出了大量努力，但目前尚无FDA批准的药物可用于治疗可卡因滥用或依赖。可卡因使用的一个突出特点是成瘾者复吸率高。可卡因渴求被认为是复吸前的一个重要事件，可以通过呈现可卡因相关线索在人类成瘾者中引起。同样，可卡因配对线索能够恢复先前熄灭的可卡因寻求行为在实验动物训练自我管理可卡因。最近在啮齿类动物中获得的证据表明，II组代谢型谷氨酸受体（mGluRs）的激活能够减弱可卡因线索诱导恢复的能力。II组mGluR包括mGluR 2和mGluRS亚型，并且是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。这些受体位于已知参与可卡因强化效应的大脑区域，如尾状核、丘脑核（NAcc）、前额皮质和杏仁核。拟议的实验试图将早期的研究结果从啮齿动物转化和扩展到可卡因使用和复发的非人类灵长类动物模型。将训练松鼠猴在存在不同环境刺激的情况下自我静脉注射可卡因。因此，在生理盐水替代试验期间，这些刺激的呈现将导致可卡因寻求行为的启动和维持，而不是可卡因本身的直接药理作用。在线索呈递测试之前，将用高选择性和有效的II组mGluR激动剂LY 379268预处理动物，以确定这些受体的激活是否可以减弱具有广泛可卡因自我给药史的灵长类动物中线索诱导的药物寻求行为。随后，动物将植入导向套管，靶向纹状体的背侧和腹侧（NAcc）部分。提示呈现测试阶段将与微透析同时进行，以评估LY 379268对可卡因寻求的影响与其对背侧和腹侧纹状体内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相关性。本研究的目的是更好地了解药物相关线索能够引起可卡因成瘾者药物渴求的机制。由于渴望是药物使用复发前的一个主要因素，这些实验的结果可能有助于确定新的目标，为anticaving和复发预防药物的发展。

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.