Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters.
Benjamin M Williams, Nathan D Steed, Joel T Woolley, Aubrey A Moedl, Christina A Nelson, Gavin C Jones, Matthew D Burris, Hugo R Arias, Oc-Hee Kim, Eun Young Jang, Arik J Hone, J Michael Mcintosh, Jordan T Yorgason, Scott C Steffensen
ACS Chemical Neuroscience May 1, 2024 DOI: 10.1021/acschemneuro.3c00478 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice and male Sprague-Dawley rats |
| Interventions | catharanthine 18-methoxycoronaridine (18-MC) |
| Topics | Addiction |
| Keywords | 18-methoxycoronaridine Catharanthine Nicotinic acetylcholine receptors Nucleus accumbens core Self-administration Combat nicotine addiction Reduced nicotine-seeking behaviors Natural compound Influencing dopamine pathways Neuroscience methods: voltammetry Using voltammetry |
| Citations | 7 |
| Key findings | Catharanthine and 18-MC reduce nicotine-induced dopamine release, locomotor activity, and self-administration, but catharanthine combined with nicotine may produce hallucinogenic effects. |
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.