Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters

• DOI: 10.1021/acschemneuro.3c00478
• Publication Date: 2024-04-13T12:01:28Z
• Authors: 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
• Keywords: Male; Nicotine; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Dopamine; Self Administration; Nicotinic Antagonists; Receptors, Nicotinic; Motor Activity; Synaptic Transmission; Nucleus Accumbens; Mice, Inbred C57BL; Mice; Xenopus laevis; Interneurons; Ibogaine; Oocytes; Animals; Nicotinic Agonists

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective this study was to evaluate effects catharanthine 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission cholinergic interneurons mesolimbic DA system, nicotine-induced locomotor activity, nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) nucleus accumbens core male mice, we found that or 18-MC differentially inhibited evoked release. Catharanthine inhibition release significantly reduced by both α4 α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, substantially increased more than vehicle during high-frequency stimulation, although less potently an nAChR antagonist, which confirms previous work with Interestingly, while slowed reuptake measured via FSCV vivo, it extracellular striatal dialysate from anesthetized mice a dose-dependent manner. Superfusion firing rate concentration dependent manner, are modulate presynaptic suppressed currents oocytes expressing recombinant rat α6/α3β2β3 α6/α3β4 nAChRs. In behavioral experiments using Sprague-Dawley rats, systemic administration blocked nicotine enhancement activity. Importantly, attenuated self-administration manner having no effect food reinforcement. Lastly, together greatly head twitch responses, indicating potential synergistic hallucinogenic effect. These findings demonstrate similar, but not identical dynamics, interneuron activity psychomotor effects.