Galanin-opiate interactions

描述（由申请人提供）：我们已经证明神经肽甘丙肽是针对小鼠中阿片成瘾的行为和神经化学相关物的保护因子，包括吗啡诱导的运动激活、条件性位置偏爱和戒断。因此，甘丙肽激动剂将是潜在的药物制剂，以减少阿片类药物的滥用倾向和甘丙肽相关基因的多态性可能会使个人的药物滥用。我们发现甘丙肽基因敲除小鼠表现出增加的吗啡诱导的运动和条件性位置偏爱（CPP），并且这些行为表型与通过腹侧被盖区（VTA）和下游靶区域（包括延髓核（NAc）和杏仁核）中的细胞外调节激酶（ERK）增加的细胞内信号传导相关。我们假设甘丙肽通常会降低中脑边缘系统的活性，直接通过对多巴胺（DA）神经元的影响或间接通过对乙酰胆碱（ACh）释放的影响，并且降低甘丙肽活性会增加对吗啡的敏感性。该提案将通过评估甘丙肽调节纹状体/NAc突触体释放DA和ACh的能力，并测量甘丙肽治疗的野生型小鼠和缺乏甘丙肽的敲除小鼠（Gal-KO）对吗啡的反应，来研究甘丙肽对吗啡诱导的运动和位置偏爱的作用机制。我们将确定甘丙肽是否可以调节乙酰胆碱的活性在切片中，乙酰胆碱是否是重要的超敏反应，以吗啡CPP在Gal-KO小鼠。我们将使用缺乏不同甘丙肽受体亚型的基因敲除小鼠来鉴定对于其降低吗啡CPP的能力重要的受体。最后，我们假设，如果甘丙肽调节mesolimbic兴奋性，它也将是对其他类别的成瘾药物的行为影响的保护，所以我们将确定可卡因诱导的运动和CPP是否在Gal-KO小鼠改变。这些研究将是至关重要的特征，一个重要的保护因素，可能会防止药物成瘾的发展。我们已经证明甘丙肽可能是一个重要的保护因素，对阿片类药物成瘾的发展。由于我们已经表明甘丙肽可以抵消吗啡奖赏和吗啡戒断，甘丙肽激动剂将是有趣的药理学试剂，以减少阿片类药物的滥用倾向，用于疼痛和治疗成瘾者谁是试图成为禁欲。此外，与甘丙肽信号相关的遗传因素可能是个体是否易患阿片类药物成瘾的重要决定因素。

DESCRIPTION (provided by applicant): We have shown that the neuropeptide galanin is a protective factor against behavioral and neurochemical correlates of opiate addiction in mice, including morphine-induced locomotor activation, conditioned place preference and withdrawal. Thus, galanin agonists would be potential pharmacological agents to decrease the abuse liability of opiates and polymorphisms in galanin-related genes might predispose individuals to drug abuse. We have found that galanin knockout mice show increased morphine-induced locomotion and conditioned place preference (CPP), and that these behavioral phenotypes are correlated with increased intracellular signaling through extracellular-regulated kinase (ERK) in the ventral tegmental area (VTA) and downstream target regions including the nucleus accumbens (NAc) and amygdala. We hypothesize that galanin normally decreases activity of the mesolimbic system, either directly through effects on dopamine (DA) neurons or indirectly through effects on acetylcholine (ACh) release, and that decreasing galanin activity increases sensitivity to morphine. This proposal will investigate the mechanisms responsible for the effects of galanin on morphine-induced locomotion and place preference by evaluating the ability of galanin to modulate DA and ACh release from striatal/NAc synaptosomes and measuring DA and ACh release in response to morphine in wild type mice treated with galanin and knockout mice lacking galanin (Gal-KO). We will determine whether galanin can modulate ACh activity in slices, and whether ACh is important for the hypersensitivity to morphine CPP in Gal-KO mice. We will identify the receptors important for its ability to decrease morphine CPP using knockout mice lacking different galanin receptor subtypes. Finally, we hypothesize that if galanin modulates mesolimbic excitability, it will also be protective against behavioral effects of other classes of addictive drugs, so we will determine whether cocaine-induced locomotion and CPP are altered in Gal-KO mice. These studies will be critical in characterizing an important protective factor that may protect against the development of drug addiction. We have shown that galanin is likely to be an important protective factor against the development of opiate addiction. Since we have shown that galanin can counteract both morphine reward and morphine withdrawal, galanin agonists would be interesting pharmacological agents to decrease the abuse liability of opiates prescribed for pain and to treat addicts who are attempting to become abstinent. In addition, genetic factors related to galanin signaling could be important determinants of whether individuals are susceptible to opiate addiction.