Galanin-opiate interactions

描述（由申请人提供）：我们已经证明神经肽甘丙氨酸是一种保护因子，可以防止小鼠阿片成瘾的行为和神经化学相关反应，包括吗啡诱导的运动激活、条件性位置偏好和戒断。因此，甘丙肽激动剂可能是减少阿片类药物滥用的潜在药物，甘丙肽相关基因的多态性可能使个体容易滥用药物。我们发现，丙氨酸敲除小鼠表现出吗啡诱导的运动和条件性位置偏好（CPP）增加，这些行为表型与腹侧被盖区（VTA）和下游靶区（包括伏隔核（NAc）和杏仁核）通过细胞外调节激酶（ERK）增加的细胞内信号传导相关。我们假设丙氨酸通常会通过直接影响多巴胺（DA）神经元或间接影响乙酰胆碱（ACh）释放而降低中脑边缘系统的活性，并且丙氨酸活性的降低会增加对吗啡的敏感性。本研究将通过评估甘丙肽调节纹状体/NAc突触体DA和ACh释放的能力，以及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）对吗啡的反应中DA和ACh的释放，来研究甘丙肽对吗啡诱导的运动和位置偏好的影响机制。我们将研究甘丙氨酸是否能调节肝切片中乙酰胆碱的活性，以及乙酰胆碱是否在Gal-KO小鼠吗啡CPP超敏反应中起重要作用。我们将使用缺乏不同丙氨酸受体亚型的敲除小鼠来确定其降低吗啡CPP能力的重要受体。最后，我们假设，如果甘丙氨酸调节中脑边缘兴奋性，它也会对其他类成瘾药物的行为影响有保护作用，因此我们将确定可卡因诱导的运动和CPP是否在Gal-KO小鼠中发生改变。这些研究对于确定可能防止药物成瘾发展的重要保护因素至关重要。我们已经证明丙氨酸可能是防止阿片类药物成瘾发展的重要保护因素。由于我们已经证明甘丙肽可以抵消吗啡奖励和吗啡戒断，甘丙肽激动剂将是一种有趣的药物制剂，可以减少处方阿片类药物的滥用，并治疗试图戒断的成瘾者。此外，与丙氨酸信号传导相关的遗传因素可能是个体是否易受阿片类药物成瘾影响的重要决定因素。

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.