EFFECTS OF MGLUR2/3 ACTIVATION ON CUE-INDUCED COCAINE RELAPSE IN SQUIRREL MONKEY

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。 该项目的目的是更好地了解毒品相关线索能够诱导可卡因滥用者寻求药物行为的机制，以及确定治疗可卡因成瘾和复发的药物治疗靶点。我们建议对非人类灵长类动物进行一种新的操作条件反射程序的培训，通过这种程序，环境刺激可以预测静脉注射可卡因(S+)或生理盐水(S-)。早期实验表明，II组代谢性谷氨酸受体激动剂LY479268选择性地减少药物相关刺激引起的反应。然而，由于其固有的复杂性，这种行为时间表被证明很难纳入足够数量的实验对象，因此我们修改了我们的实验程序。一大批受试者现在按照更传统的二级可卡因自我给药时间表进行训练，该时间表缺乏S+/S-偶然性，我们将使用恢复程序作为线索或药物诱导复吸的模型。此外，由于LY379268出现不良副作用以及其对多巴胺D2受体的作用，我们已经停止了对LY379268的研究。我们已经开始了初步研究，研究其他药理靶点，特别是5-羟色胺(5-羟色胺)2a和2c受体。到目前为止，我们已经证明，全身应用5-HT2c受体激动剂mCPP或RO60-0175可以减弱可卡因的行为刺激和复发诱导效应。目前的研究正在使用自我给药程序调查这些化合物对可卡因增强效果的影响。

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 purpose of this project is to better understand the mechanisms by which drug-associated cues are capable of eliciting drug-seeking behavior in cocaine abusers, as well as to identify pharmacotherapeutic targets for the treatment of cocaine addiction and relapse. We proposed to train nonhuman primates on a novel operant-conditioning procedure whereby environmental stimuli are predictive of either intravenous cocaine (S+) or saline (S-) infusions. Early experiments demonstrated that the group II metabotropic glutamate receptor agonist LY479268 selectively reduced responding elicited by drug-associated stimuli. However, this behavioral schedule proved difficult to entrain in an adequate number of experimental subjects due to its inherent complexity, and we have therefore modified our experimental procedures. A full cohort of subjects are now trained according to a more traditional schedule of second-order cocaine self-administration that lacks the S+/S- contingency, and we will use the reinstatement procedure as our model of cue- or drug-induced relapse. Additionally, we have halted our work with LY379268 due to the appearance of adverse side effects as well as its reported actions at dopamine D2 receptors. We have begun pilot studies investigating other pharmacological targets, specifically the serotonin (5-HT) 2a and 2c receptors. To date, we have demonstrated that systemic administration of the 5-HT 2c receptor agonists mCPP or Ro 60-0175 attenuates the behavioral-stimulant and relapse-inducing effects of cocaine. Current studies are investigating the effects of these compounds on the reinforcing effects of cocaine using self-administration procedures.