Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT 06508, United States.
Pharmacol Biochem Behav. 2011 Mar;98(1):87-93. doi: 10.1016/j.pbb.2010.12.015. Epub 2010 Dec 21.
Previous work has indicated that the neuropeptide galanin decreases sensitivity to the rewarding effects of morphine and cocaine, but increases alcohol drinking. The aim of the current study was to examine the role of galanin signaling in nicotine reward by testing the effects of nicotine in mice lacking galanin peptide (GAL-/-) as compared to wild-type (GAL+/+) controls. Using an unbiased, three-chamber conditioned place preference (CPP) paradigm the dose-response function for nicotine CPP was tested in GAL-/- and GAL+/+ mice. Since activation of extracellular signal-related kinase (ERK2) is involved in the rewarding effects of several classes of drugs of abuse, we then measured the level of ERK2 phosphorylation in the nucleus accumbens shell (NACsh) and core (NACco) of GAL-/- and GAL+/+ mice following re-exposure to the CPP chamber previously paired with nicotine as a marker of mesolimbic system activation. Finally, we examined whether acute nicotine administration affects ERK2 activity in GAL-/- and GAL+/+ mice. GAL-/- mice required a higher dose of nicotine to induce a significant CPP compared to GAL+/+ mice. In the conditioning groups showing significant expression of nicotine CPP, only GAL+/+ mice showed ERK2 activation in the NACsh. This suggests that the nicotine CPP observed in GAL+/+ mice resulted in differential recruitment of ERK signaling in the NACsh compared to GAL-/- mice. In addition, no activation of ERK2 was observed following acute nicotine administration in either genotype. These data, along with prior results, suggest that galanin alters sensitivity to drugs of abuse differentially, with morphine, cocaine and amphetamine place preference suppressed, and nicotine and alcohol preference increased, by galanin signaling.
先前的工作表明，神经肽甘丙肽降低了对吗啡和可卡因的奖赏效应的敏感性，但增加了酒精的摄入。本研究的目的是通过测试缺乏甘丙肽肽（GAL-/-）的小鼠与野生型（GAL+/+）对照相比，尼古丁的奖赏作用中的甘丙肽信号作用，来检验甘丙肽信号作用在尼古丁奖赏中的作用。使用无偏、三腔条件性位置偏好（CPP）范式，测试了 GAL-/-和 GAL+/+小鼠中尼古丁 CPP 的剂量反应函数。由于细胞外信号调节激酶（ERK2）的激活涉及几种滥用药物的奖赏作用，因此我们随后测量了重新暴露于先前与尼古丁配对的 CPP 室后，GAL-/-和 GAL+/+小鼠中伏隔核壳（NACsh）和核心（NACco）中的 ERK2 磷酸化水平，作为中脑边缘系统激活的标志物。最后，我们检查了急性尼古丁给药是否会影响 GAL-/-和 GAL+/+小鼠中的 ERK2 活性。与 GAL+/+ 小鼠相比，GAL-/- 小鼠需要更高剂量的尼古丁才能诱导明显的 CPP。在表现出明显的尼古丁 CPP 的调节组中，只有 GAL+/+ 小鼠在 NACsh 中显示出 ERK2 的激活。这表明，与 GAL-/- 小鼠相比，在 GAL+/+ 小鼠中观察到的尼古丁 CPP 导致了 NACsh 中 ERK 信号的不同招募。此外，在两种基因型中，急性尼古丁给药后均未观察到 ERK2 的激活。这些数据以及先前的结果表明，甘丙肽信号作用以不同的方式改变了对药物滥用的敏感性，甘丙肽信号作用抑制了吗啡、可卡因和安非他命的位置偏好，增加了尼古丁和酒精的偏好。
