Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Malaga, Spain.
Department of Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
Addict Biol. 2018 Mar;23(2):723-734. doi: 10.1111/adb.12531. Epub 2017 Jun 29.
Nicotine exerts its rewarding effects by promoting an increase in dopamine (DA) release in the nucleus accumbens (NAc), and this process is influenced by the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is the main enzyme responsible for the degradation of the endocannabinoid anandamide and other non-cannabinoid N-acylethanolamines. Previous research has reported that both genetic deletion and pharmacological inhibition of FAAH enhance nicotine-induced conditioned place preference at low doses. We conducted a microdialysis study to characterize nicotine-induced changes in DA and serotonin (5-HT) levels in the NAc of FAAH knockout (KO) mice using a conditioned place preference-like paradigm with three nicotine doses (0.1, 1 and 10 mg/kg, s.c.). Additionally, the effects of the selective FAAH inhibitor PF-3845 (10 mg/kg, i.p.) were also examined. Our data indicated that compared with wild-type mice, genetic deletion of FAAH selectively enhanced the effect of low-dose nicotine on DA release (p < 0.001) and resulted in a strong post-nicotine elevation in DA levels (p < 0.01). However, there were no differences between the genotypes at higher doses. Furthermore, FAAH KO mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.05), with no differences between the genotypes at higher doses. Compared with vehicle-pretreated mice, mice pretreated with PF-3845 displayed an enhancement of the effect of low-dose nicotine on NAc DA release (p < 0.001), which resulted in a sustained increase in DA levels (p < 0.05). Similar to FAAH KO mice, PF-3845-pretreated mice displayed a moderate enhancement of the effect of low-dose nicotine on NAc 5-HT release (p < 0.01). These observations in mice suggest that enhanced nicotine-induced NAc DA release might contribute to increased sensitivity to the conditioned rewarding effects of low-dose nicotine following FAAH inhibition, which has been previously reported. Future studies combining behavioral and neurochemical approaches are needed to elucidate the precise mechanism of these effects.
尼古丁通过促进伏隔核（NAc）中多巴胺（DA）的释放来发挥其奖赏作用，而这一过程受到内源性大麻素系统的影响。脂肪酸酰胺水解酶（FAAH）是负责降解内源性大麻素大麻素酰胺和其他非大麻素 N-酰基乙醇胺的主要酶。先前的研究报告称，FAAH 的基因缺失和药理学抑制均可增强低剂量尼古丁诱导的条件性位置偏好。我们使用类似条件性位置偏好的范式，通过三种尼古丁剂量（0.1、1 和 10 mg/kg，sc），在 FAAH 敲除（KO）小鼠中进行了微透析研究，以表征尼古丁诱导的 NAc 中 DA 和 5-羟色胺（5-HT）水平的变化。此外，还检查了选择性 FAAH 抑制剂 PF-3845（10 mg/kg，ip）的作用。我们的数据表明，与野生型小鼠相比，FAAH 的基因缺失选择性增强了低剂量尼古丁对 DA 释放的作用（p < 0.001），并导致 DA 水平在尼古丁后显著升高（p < 0.01）。然而，在较高剂量下，两种基因型之间没有差异。此外，FAAH KO 小鼠对低剂量尼古丁对 NAc 5-HT 释放的作用表现出适度增强（p < 0.05），而在较高剂量下，两种基因型之间没有差异。与 vehicle 预处理的小鼠相比，用 PF-3845 预处理的小鼠对低剂量尼古丁对 NAc DA 释放的作用增强（p < 0.001），导致 DA 水平持续升高（p < 0.05）。与 FAAH KO 小鼠类似，PF-3845 预处理的小鼠对低剂量尼古丁对 NAc 5-HT 释放的作用也表现出适度增强（p < 0.01）。这些在小鼠中的观察结果表明，增强的尼古丁诱导的 NAc DA 释放可能有助于 FAAH 抑制后增加对低剂量尼古丁的条件性奖赏作用的敏感性，这在以前的研究中已经报道过。需要结合行为和神经化学方法的未来研究来阐明这些作用的确切机制。
