Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States.
Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, Oklahoma 74464, United States.
ACS Chem Neurosci. 2024 May 1;15(9):1738-1754. doi: 10.1021/acschemneuro.3c00478. Epub 2024 Apr 13.
Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV , it also increased extracellular DA in striatal dialysate from anesthetized mice in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3β2β3 or α6/α3β4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.
伊波加因生物碱，也称为冠狗尾草碱同系物，在治疗酒精和阿片类药物使用障碍方面显示出了潜力。本研究的目的是评估石蒜科生物碱和 18-甲氧基冠狗尾草碱（18-MC）对中脑边缘多巴胺系统中多巴胺（DA）传递和胆碱能中间神经元、尼古丁诱导的运动活动和尼古丁摄入行为的影响。我们利用雄性小鼠伏隔核核心的快速扫描循环伏安法（FSCV）发现，石蒜科生物碱或 18-MC 可差异抑制诱发的 DA 释放。α4 和 α6 烟碱型乙酰胆碱受体（nAChR）拮抗剂均显著降低了石蒜科生物碱对诱发的 DA 释放的抑制作用。此外，与载体相比，石蒜科生物碱在高频刺激时可显著增加 DA 释放，尽管其效力不及 α4 nAChR 拮抗剂，但与以前使用 nAChR 拮抗剂的工作结果一致。有趣的是，虽然石蒜科生物碱通过 FSCV 减缓了 DA 的再摄取，但它也以剂量依赖的方式增加了麻醉小鼠纹状体透析液中的细胞外 DA。石蒜科生物碱或 18-MC 的灌流以浓度依赖的方式抑制纹状体胆碱能中间神经元的放电率，这已知可强烈调节突触前 DA 释放。石蒜科生物碱或 18-MC 抑制在表达重组大鼠 α6/α3β2β3 或 α6/α3β4 nAChR 的卵母细胞中表达的乙酰胆碱电流。在使用雄性 Sprague-Dawley 大鼠的行为实验中，全身性给予石蒜科生物碱或 18-MC 阻断了尼古丁对运动活动的增强作用。重要的是，石蒜科生物碱以剂量依赖的方式减弱了尼古丁的自我给药，而对食物强化没有影响。最后，石蒜科生物碱和尼古丁一起给药大大增加了头部抽搐反应，表明存在潜在的协同致幻作用。这些发现表明，石蒜科生物碱和 18-MC 对纹状体 DA 动力学、纹状体胆碱能中间神经元活性和尼古丁精神运动效应具有相似但不完全相同的作用。
