Abstract：
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 ex vivo 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 ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo 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.
摘要：
伊博加生物碱，也被称为coronaridine同源物，在治疗酒精和阿片类药物使用障碍方面表现出了希望。这项研究的目的是评估catharanthine和18-甲氧基coronaridine（18-MC）对中脑边缘DA系统中多巴胺（DA）传递和胆碱能中间神经元的影响，尼古丁诱导的运动活动，和服用尼古丁的行为。利用雄性小鼠伏隔核的离体快速扫描循环伏安法（FSCV），我们发现catharanthine或18-MC差异抑制诱发的DA释放。α4和α6烟碱乙酰胆碱受体（nAChRs）拮抗剂显着降低了对诱发DA释放的Catharanthine抑制。此外,在高频刺激过程中，与媒介物相比，卡瓦罗素显著增加了DA的释放，虽然不如α4nAChR拮抗剂有效，这证实了以前使用nAChR拮抗剂的工作。有趣的是,虽然通过FSCV离体测量，Cosaranthine减缓了DA的再摄取，它还以剂量依赖性方式增加体内麻醉小鼠纹状体透析液中的细胞外DA。Catharanthine或18-MC的超融合以浓度依赖性方式抑制纹状体胆碱能中间神经元的放电速率，已知可有效调节突触前DA释放。Catharanthine或18-MC抑制表达重组大鼠α6/α3β2β3或α6/α3β4nAChRs的卵母细胞中的乙酰胆碱电流。在使用雄性Sprague-Dawley大鼠的行为实验中，全身给药catharanthine或18-MC可阻止尼古丁增强运动活性。重要的是,catharanthine以剂量依赖的方式减弱了尼古丁的自我给药，而对食物增强没有影响。最后,加药和尼古丁一起极大地增加了头部抽搐反应，表明潜在的协同致幻作用。这些发现表明，卡塔兰氨酸和18-MC具有相似的，但对纹状体DA动力学的影响不相同，纹状体胆碱能中间神经元活性和尼古丁精神运动效应。
