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.