Abstract
Rationale and objectives
Desensitization of neuronal nicotinic acetylcholine receptors holds promise as an effective treatment of tobacco addiction. Previously, we found that sazetidine-A (Saz-A), which selectively desensitizes α4β2 nicotinic receptors, significantly decreased intravenous (IV) nicotine self-administration (SA) in rats with an effective dose of 3 mg/kg in acute and repeated injection studies. We also found that chronic infusions of Saz-A at doses of 2 and 6 mg/kg/day significantly reduced nicotine SA in rats. In continuing studies, we have characterized other Saz-A analogs, YL-2-203 and VMY-2-95, to determine their efficacies in reducing nicotine SA in rats.
Methods
Young adult female Sprague-Dawley rats were fitted with IV catheters and were trained for nicotine SA (0.03 mg/kg/infusion) on a fixed ratio 1 schedule for ten sessions. The same rats were also implanted subcutaneously with osmotic minipumps to continually deliver 2 or 6 mg/kg body weight YL-2-203, VMY-2-95, or saline for four consecutive weeks.
Results
Chronic administration of VMY-2-95 at doses of 2 and 6 mg/kg/day caused significant (p < 0.01) decreases in nicotine SA over the 2 weeks of continued nicotine SA and for the 1-week period of resumed access after a week of enforced abstinence, whereas chronic administration of YL-2-203 at the same doses was not found to be effective.
Conclusions
These studies, together with our previous studies of Saz-A, revealed a spectrum of efficacies for these α4β2 nicotinic receptor desensitizing agents and provide a path forward for the most effective compounds to be further developed as possible aids to smoking cessation.
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Acknowledgements
This research was supported by a grant from the NIDA DA027990.
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All studies were conducted in accordance with the regulations outlined by the Duke University Animal Care and Use Committee.
Conflict of interest
AH Rezvani, VM Yenugonda, Y Liu, ML Brown, Y Xiao, KJ Kellar and ED Levin hold patents on the drugs VMY-2-95 and YL-2-203.
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Rezvani, A.H., Slade, S., Wells, C. et al. Differential efficacies of the nicotinic α4β2 desensitizing agents in reducing nicotine self-administration in female rats. Psychopharmacology 234, 2517–2523 (2017). https://doi.org/10.1007/s00213-017-4641-6
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DOI: https://doi.org/10.1007/s00213-017-4641-6