Powell Gregory L, Leyrer-Jackson Jonna M, Goenaga Julianna, Namba Mark D, Piña Jose, Spencer Sade, Stankeviciute Neringa, Schwartz Danielle, Allen Nicholas P, Del Franco Armani P, McClure Erin A, Olive Michael Foster, Gipson Cassandra D
Department of Psychology, Arizona State University, Tempe, Arizona.
School of Life Sciences, Arizona State University, Tempe, Arizona.
Physiol Rep. 2019 Jan;7(1):e13958. doi: 10.14814/phy2.13958.
N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.
N-乙酰半胱氨酸（NAC）是一种很有前景的谷氨酸能治疗药物，已显示出在减少人类尼古丁使用方面的一些临床疗效，并且已被证明能逆转药物引起的谷氨酸能神经生理学变化。在大鼠中，觅烟行为与伏隔核核心区（NAcore）内谷氨酸能可塑性的改变有关。具体而言，线索诱导的觅烟行为与NAcore中型多棘神经元上谷氨酸能突触的快速、短暂突触可塑性（t-SP）有关。本研究的目的是确定NAC是否能减少觅烟行为并逆转与复吸相关的NAcore谷氨酸能改变。大鼠停止尼古丁自我给药后，在线索诱导复吸前4天进行亚慢性NAC给药（0或100mg/kg/d）。通过树突棘形态测量NAcore突触增强，并对相关谷氨酸能基因的mRNA和蛋白质进行定量。亚慢性NAC治疗并未减少觅烟行为。此外，亚慢性NAC对多个谷氨酸能基因的NAcore转录本和蛋白质表达以及棘形态测量均无影响。最后，与赋形剂相比，在消退期和复吸前进行慢性NAC治疗（共15天）显著降低了消退反应并减少了尼古丁觅求行为的复吸。总之，这些结果表明，慢性NAC治疗作为尼古丁成瘾和复吸的治疗策略，其治疗效果是必要的。
