| Autor: |
Williams BM; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Steed ND; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Woolley JT; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Moedl AA; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Nelson CA; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Jones GC; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Burris MD; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Arias HR; Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, Oklahoma 74464, United States., Kim OH; Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea., Jang EY; Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea., Hone AJ; George E. Wahlen Veterans Affairs Medical Center, and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, Utah 84112, United States., McIntosh JM; George E. Wahlen Veterans Affairs Medical Center, and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, Utah 84112, United States., Yorgason JT; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States., Steffensen SC; Department of Psychology/Neuroscience, Brigham Young University, Provo, Utah 84602, United States. |
| Abstrakt: |
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. |
