ORPHANIN FQ AND COCAINE SENSITIZATION

孤啡肽 FQ 和可卡因致敏作用

基本信息

批准号：
6378299
负责人：
KABIRULLAH LUTFY
金额：
$ 12.12万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2003-06-30
项目状态：
已结题

项目摘要

Orphanin FQ (OFQ), has been identified as the endogenous ligand of the opioid receptor-like (ORL-1) receptor. Although this peptide and its receptor show structural similarities to their opioid counterparts, OFQ has been shown to exert counter-opioid effects in the brain. OFQ has been reported to decrease motor behavior and extracellular levels of dopamine in the nucleus accumbens following intracerebroventricular injection. These data suggest that OFQ may be important in the regulation of endogenous "reward" pathways. We propose to evaluate the acute and chronic actions of this peptide on cocaine-induced dopamine release in the forebrain using microdialysis in freely moving rats, concomitant with measurement of motor behavior, and to determine the site of action of OFQ along the mesocorticolimbic axis. Repeated intermittent cocaine administration induces a phenomenon of behavioral and neurochemical sensitization which may be important in cocaine craving and addiction. This is associated with an increased dopamine release response in the nucleus accumbens. In addition to changes in dopamine release, hyperactivity of glutamatergic neurons has also been implicated in the effects of cocaine. Indeed, the development of cocaine sensitization (mediated in the ventral tegmental area, VTA) can be prevented by NMDA receptor antagonists. Since, in addition to its action on dopamine systems, OFQ has also been shown to inhibit glutamate release in some brain regions, we hypothesize that OFQ may prove particularly potent in blocking cocaine sensitization. We therefore propose to examine the effect of OFQ on cocaine-induced behavioral sensitization and accompanying changes in glutamate and dopamine release in the VTA and nucleus accumbens. The studies proposed will further our understanding of the role of this new peptide in the modulation of reward circuitry in general and on cocaine actions on these pathways in particular. Based on these findings, it may be possible in the future to develop anti- craving compounds for use in the treatment of psychostimulant abuse.

孤啡肽 FQ (OFQ) 已被确定为阿片受体样 (ORL-1) 受体的内源性配体。尽管这种肽及其受体与阿片类药物的对应物结构相似，但 OFQ 已被证明可以在大脑中发挥反阿片类药物的作用。据报道，脑室内注射后，OFQ 可降低伏隔核中的运动行为和细胞外多巴胺水平。这些数据表明 OFQ 可能在内源性“奖励”途径的调节中发挥重要作用。我们建议使用微透析在自由活动的大鼠中评估该肽对可卡因诱导的前脑多巴胺释放的急性和慢性作用，同时测量运动行为，并确定 OFQ 沿中皮质边缘轴的作用位点。反复间歇性服用可卡因会诱发行为和神经化学过敏现象，这可能对可卡因渴望和成瘾很重要。这与伏隔核中多巴胺释放反应的增加有关。除了多巴胺释放的变化之外，谷氨酸能神经元的过度活跃也与可卡因的作用有关。事实上，NMDA 受体拮抗剂可以预防可卡因致敏（由腹侧被盖区 VTA 介导）的发生。由于除了对多巴胺系统的作用外，OFQ 还被证明可以抑制某些大脑区域的谷氨酸释放，因此我们假设 OFQ 在阻止可卡因致敏方面可能特别有效。因此，我们建议检查 OFQ 对可卡因诱导的行为敏化以及 VTA 和伏核中谷氨酸和多巴胺释放的伴随变化的影响。所提出的研究将进一步加深我们对这种新肽在奖励回路调节中的作用的理解，特别是可卡因对这些途径的作用。基于这些发现，将来有可能开发出用于治疗精神兴奋剂滥用的抗渴求化合物。