Methoxsalen inhibited the acquisition of nicotine self-administration: attenuation by cotinine replacement in rats.
Methoxsalen inhibited the acquisition of nicotine self-administration: attenuation by cotinine replacement in rats.
复制标题
甲氧沙林抑制自我给药尼古丁的获得：大鼠体内通过可替宁替代而减弱。
DOI：
10.1101/2023.06.04.543614
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Tan,Xiaoying
中科院分区：
文献类型：
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作者：
Ding,Zheng-Ming;Neslund,ElizabethM;Sun,Dongxiao;Tan,Xiaoying
吸烟仍然是导致疾病和死亡的主要可预防原因。尼古丁是香烟中维持成瘾的主要增强成分。可替宁是尼古丁的主要代谢产物，可产生多种神经行为效应。可替宁支持自我给药，有静脉自我给药可替宁史的大鼠表现出类似复发的药物寻求行为，表明可替宁也可能具有强化作用。迄今为止，可替宁对尼古丁强化的潜在贡献仍然未知。大鼠体内尼古丁代谢主要由肝脏 CYP2B1 酶催化，甲氧沙林是一种有效的 CYP2B1 抑制剂。该研究测试了甲氧沙林抑制尼古丁代谢和自我给药以及可替宁替代品减弱甲氧沙林的抑制作用的假设。皮下注射尼古丁后，急性甲氧沙林可降低血浆可替宁水平并增加尼古丁水平。重复甲氧沙林减少了尼古丁自我给药的获得，导致尼古丁输注量减少、杠杆分化破坏、尼古丁总摄入量减少以及血浆可替宁水平降低。另一方面，尽管血浆可替宁水平大大降低，但在维持阶段，甲氧沙林并没有改变尼古丁的自我给药。通过将可替宁与尼古丁混合进行自我给药来替代可替宁，可剂量依赖性地增加血浆可替宁水平，抵消甲氧沙林的作用，并增强自我给药的获得。甲氧沙林均未改变基础运动活性或尼古丁诱导的运动活性。这些结果表明，甲氧沙林抑制了尼古丁的可替宁形成和尼古丁自我给药的获得，并且血浆可替宁的替代减弱了甲氧沙林的抑制作用，这表明可替宁可能有助于尼古丁强化的发展。
Cigarette smoking remains the leading preventable cause of disease and death. Nicotine is the primary reinforcing ingredient in cigarettes sustaining addiction. Cotinine is the major metabolite of nicotine that produces a myriad of neurobehavioral effects. Cotinine supported self-administration and rats with a history of intravenous self-administration of cotinine exhibited relapse-like drug-seeking behavior, suggesting cotinine may also be reinforcing. To date, a potential contribution of cotinine to nicotine reinforcement remains unknown. Nicotine metabolism is mainly catalyzed by hepatic CYP2B1 enzyme in the rat and methoxsalen is a potent CYP2B1 inhibitor. The study tested the hypothesis that methoxsalen inbibits nicotine metabolism and self-administration, and that cotinine replacement attenuates the inhibitory effects of methoxsalen. Acute methoxsalen decreased plasma cotinine levels and increased nicotine levels following subcutaneous nicotine injection. Repeated methoxsalen reduced the acquisition of nicotine self-administration, leading to fewer nicotine infusions, disruption of lever differentiation, smaller total nicotine intake, and lower plasma cotinine levels. On the other hand, methoxsalen did not alter nicotine self-administration during the maintenance phase despite great reduction of plasma cotinine levels. Cotinine replacement by mixing cotinine with nicotine for self-administration dose-dependently increased plasma cotinine levels, counteracted effects of methoxsalen, and enhanced the acquisition of self-administration. Neither basal nor nicotine-induced locomotor activity was altered by methoxsalen. These results indicate that methoxsalen depressed cotinine formation from nicotine and the acquisition of nicotine self-administration, and that replacement of plasma cotinine attenuated the inhibitory effects of methoxsalen, suggesting that cotinine may contribute to the development of nicotine reinforcement.